Anabaseine derivatives, pharmaceutical compositions and method of use thereof

ABSTRACT

Disclosed are novel anabaseine derivatives that act as agonists of the α7 nAChR. Also disclosed are pharmaceutical compositions, methods of treating inflammatory conditions, methods of treating CNS disorders, methods for inhibiting cytokine release from mammalian cells and methods for the preparation of the novel compounds.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/762,544, filed on Jan. 26, 2006. The entire teachings of the aboveapplication(s) are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gatedion channels found at the neuromuscular junction as well as throughoutthe central and peripheral nervous systems. In humans, 16 differentnAChR subunits have been identified and include α1-α7, α9-α10, β1-4, δ,ε and γ (Lindstrom, 1995. Nicotinic acetylcholine receptors in “Handbookof Receptors and Channels: Ligand- and Voltage-Gated Ion Channels.”Edited by R. Alan North. CRC Press, Inc.). These subunits canco-assemble to form numerous homo- and heteropentameric subtypes whichin turn are characterized by distinct ligand-binding and pharmacologicproperties (Lindstrom, 1995).

The α7 nAChR subtype has been reported to play a role in severaldiseases of the central nervous system (CNS) including Alzheimer'sdisease (Wang et al, J Biol. Chem. 275(8): 5626-32 (2000), Kem, BrainBiol. Res. 113(1-2): 169-81 (2000)), schizophrenia (Adler et al,Schizophr Bull 24(2):189-202 (1998)), Parkinson's disease (Quik et al,Eur J Pharm 393(1-3) 223-30 (2000)) and attention deficit-hyperactivitydisorder (Wilens et al, Am J Psychiatry 156(12): 1931-7 (1999), Levin etal, Eur J Pharmacol. 393(1-3): 141-6 (2000)). Selective agonists of theα7 nAChR subtype have therefore been proposed as useful for thetreatment of these and other central nervous system conditions (U.S.Pat. Nos. 6,110,914, 5,902,814, 6,599,916, 6,432,975; Kem et al, Behav.Brain Res. 113(1-2): 169-81 (2000), Martin et al, Psychopharmacology,Feb. 19 (2004)).

The α7 nAChR subtype has also recently been shown to have involvement inthe inflammatory response (Wang et al, Nature, 421(6921):384-8 (2003)).Wang et al demonstrated that activation of the α7 nAChR inhibits therelease of proinflammatory cytokines, such as tumor necrosis factoralpha (TNF-α) and high mobility group box 1 protein (HMGB1), frommacrophage cells and confers protection against lethality in a murinemodel of sepsis. Selective agonists of α7 nAChRs have been demonstratedto have utility as anti-inflammatory agents by inhibiting the release ofTNF-α and other proinflammatory cytokines (WO 2004/052365 A2).

Given the therapeutic potential of α7 nAChR agonists in the treatment ofinflammatory conditions, CNS conditions as well as other deleteriousconditions, there remains a need in the art for additional α7 nAChRagonists.

SUMMARY OF THE INVENTION

It has now been discovered that certain novel anabaseine derivatives actas agonists of the δ7 nAChR. Based on this discovery, novel compounds,pharmaceutical compositions, methods of treating inflammatoryconditions, methods of treating CNS disorders, methods for inhibitingcytokine release from mammalian cells and methods for the preparation ofthe novel compounds are disclosed.

In one embodiment, the invention pertains to a compound of the Formula(I):

or a pharmaceutically acceptable salt thereof, wherein:

A is selected from the group consisting of R₁ and R₂;

Each D is independently selected from the group consisting of C1-C10alkyl, C1-C10 alkyl substituted with one or more R₈, C2-C10 alkenyl,C2-C10 alkenyl substituted with one or more R₈, C2-C10 alkynyl, C2-C10alkynyl substituted with one or more R₈, C3-C10 cycloalkyl, C3-C10cycloalkyl substituted with one or more R₉, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₉, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₉, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₉, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₉, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₉,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₉, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₉,halo, haloalkyl, OR₇, SR₇, NR₇R₇, C(O)OR₇, NO₂, CN, C(O)R₇, C(O)C(O)R₇,C(O)NR₇R₇, C(O)C(O)NR₇R₇, N(R₇)C(O)R₇, NR₇S(O)_(q)R₇, N(R₇)C(O)OR₇,NR₇C(O)C(O)R₇, NR₇C(O)NR₇R₇, NR₇S(O)_(q)NR₇R₇, NR₇S(O)_(q)R₇,S(O)_(q)R₇, S(O)_(q)NR₇R₇, OC(O)R₇, aryl and heteroaryl, wherein saidaryl and heteroaryl are each optionally substituted with one or moreR₁₁;

R₁ is selected from the group consisting of:

R₃ is selected from the group consisting of a 6 membered monocyclic aryland 5 or 6 membered monocyclic heteroaryl comprising 1-3 heteroatoms,wherein each of said heteroatoms is independently selected from thegroup consisting of O, N and S, and wherein said aryl and heteroaryl areeach optionally substituted with one or more R₁₁;

X is selected from the group consisting of O, NR₇ and NR₇CONR₇;

R₄ is selected from the group consisting of C3-C8 cycloalkyl, C3-C8cycloalkyl substituted with one or more R₉, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₉, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₉, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₉, C5-C11 bicycloalkyl,C5-C₁₁ bicycloalkyl substituted with one or more R₉, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₉,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₉, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₉, aryland heteroaryl, wherein said aryl and heteroaryl are each optionallysubstituted with one or more R₁₁;

Each R₅ is independently selected from the group consisting of C1-C10alkyl, C1-C10 alkyl substituted with one or more R₈, C2-C10 alkenyl,C2-C10 alkenyl substituted with one or more R₈, C2-C10 alkynyl, C2-C10alkynyl substituted with one or more R₈, C3-C10 cycloalkyl, C3-C10cycloalkyl substituted with one or more R₉, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₉, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₉, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₉, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₉, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₉,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₉, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₉,halo, haloalkyl, OR₇, SR₇, NR₇R₇, C(O)OR₇, NO₂, CN, C(O)R₇, C(O)C(O)R₇,C(O)NR₇R₇, C(O)C(O)NR₇R₇, N(R₇)C(O)R₇, NR₇S(O)_(q)R₇, N(R₇)C(O)OR₇,NR₇C(O)C(O)R₇, NR₇C(O)NR₇R₇, NR₇S(O)_(q)NR₇R₇, NR₇S(O)_(q)R₇,S(O)_(q)R₇, S(O)_(q)NR₇R₇, OC(O)R₇, aryl and heteroaryl, wherein saidaryl and heteroaryl are each optionally substituted with one or moreR₁₁;

Each R₆ is independently selected from the group consisting of C1-C10alkyl, C1-C10 alkyl substituted with one or more R₈, C2-C10 alkenyl,C2-C10 alkenyl substituted with one or more R₈, C2-C10 alkynyl, C2-C10alkynyl substituted with one or more R₈, C3-C10 cycloalkyl, C3-C10cycloalkyl substituted with one or more R₉, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₉, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₉, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₉,halo, haloalkyl, OR₇, SR₇, NR₇R₇, C(O)OR₇, NO₂, CN, C(O)R₇, C(O)C(O)R₇,C(O)NR₇R₇, C(O)C(O)NR₇R₇, N(R₇)C(O)R₇, NR₇S(O)_(q)R₇, N(R₇)C(O)OR₇,NR₇C(O)C(O)R₇, NR₇C(O)NR₇R₇, NR₇S(O)_(q)NR₇R₇, NR₇S(O)_(q)R₇,S(O)_(q)R₇, S(O)_(q)NR₇R₇ and OC(O)R₇;

Each R₇ is independently selected from the group consisting of H, C1-C10alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10cycloalkenyl, 3-10 membered heterocycloalkyl, 4-10 memberedheterocycloalkenyl, haloalkyl, aryl and heteroaryl, wherein said aryland heteroaryl are each optionally substituted with one or more R₁₁;

Each R₈ is independently selected from the group consisting of halo,haloalkyl, OR₇, SR₇, C(O)R₇, OC(O)R₇, C(O)OR₇, NR₇R₇, NO₂, CN,OC(O)NR₇R₇, C(O)NR₇R₇, N(R₇)C(O)R₇, N(R₇)(COOR₇), S(O)_(q)NR₇R₇, C3-C8cycloalkyl, C4-C10 cycloalkenyl 3-8 membered heterocycloalkyl, 4-10membered heterocycloalkenyl, C5-C11 bicycloalkyl, C5-C11 bicycloalkenyl,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkenyl,aryl and heteroaryl, wherein said aryl and heteroaryl are eachoptionally substituted with one or more R₁₁;

Each R₉ is independently selected from the group consisting of R₈,C1-C10 alkyl, C1-C10 alkyl substituted with one or more R₈, C2-C10alkenyl, C2-C10 alkenyl substituted with one or more R₈, C2-C10 alkynyland C2-C10 alkynyl substituted with one or more R₈;

R₁₀ is aryl or heteroaryl, wherein said aryl and heteroaryl are eachoptionally substituted with one or more R₁₁;

Each R₁₁ is independently selected from the group consisting of C1-C10alkyl, C1-C10 alkyl substituted with one or more R₈, C2-C10 alkenyl,C2-C10 alkenyl substituted with one or more R₈, C2-C10 alkynyl, C2-C10alkynyl substituted with one or more R₈, C3-C10 cycloalkyl, C3-C10cycloalkyl substituted with one or more R₉, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₉, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₉, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₉, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₉, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₉,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₉, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₉,halo, haloalkyl, OR₇, SR₇, NR₇R₇, C(O)OR₇, NO₂, CN, C(O)R₇, C(O)C(O)R₇,C(O)NR₇R₇, N(R₇)C(O)R₇, NR₇S(O)₂R₇, N(R₇)C(O)OR₇, NR₇C(O)C(O)R₇,NR₇C(O)NR₇R₇, NR₇S(O)_(q)NR₇R₇, NR₇S(O)_(q)R₇, S(O)_(q)R₇,S(O)_(q)NR₇R₇, OC(O)R₇, optionally substituted aryl and optionallysubstituted heteroaryl;

k is an integer from 0 to 4;

m is an integer from 0 to 9;

Each n is independently an integer from 0 to 4;

Each p is independently an integer from 0 to 5; and

Each q is independently 1 or 2.

In another embodiment, the invention pertains to a compound of theFormula (II):

or a pharmaceutically acceptable salt thereof, wherein:

R₁₂ is selected from the group consisting of:

R₁₃ is selected from the group consisting of 6 membered monocyclic aryl,5 or 6 membered monocyclic heteroaryl comprising 1-3 heteroatoms, 8-12membered bicyclic aryl, 8-12 membered bicyclic heteroaryl comprising 1-6heteroatoms, 11-14 membered tricyclic aryl and 11-14 membered heteroarylcomprising 1-9 heteroatoms, wherein each of said heteroatoms isindependently selected from the group consisting of O, N and S andwherein said aryl and heteroaryl are each optionally substituted withone or more R₁₇;

Each R₁₄ is independently selected from the group consisting of H,C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10cycloalkenyl, 3-10 membered heterocycloalkyl, 4-10 memberedheterocycloalkenyl, haloalkyl aryl and heteroaryl, wherein said aryl andheteroaryl are each optionally substituted with one or more R₁₇;

Each R₁₅ is independently selected from the group consisting of halo,haloalkyl, OR₁₄, SR₁₄, C(O)R₁₄, OC(O)R₁₄, C(O)OR₁₄, NR₁₄R₁₄, NO₂, CN,OC(O)NR₁₄R₁₄, C(O)NR₁₄R₁₄, N(R₁₄)C(O)R₁₄, N(R₁₄)(COOR₁₄),S(O)_(t)NR₁₄R₁₄, C3-C8 cycloalkyl, C4-C10 cycloalkenyl, 3-8 memberedheterocycloalkyl, 4-10 membered heterocycloalkenyl, C5-C11 bicycloalkyl,C5-C11 bicycloalkenyl, 5-11 membered heterobicycloalkyl, 5-11 memberedheterobicycloalkenyl, aryl and heteroaryl, wherein said aryl andheteroaryl are each optionally substituted with one or more R₁₇;

Each R₁₆ is independently selected from the group consisting of R₁₅,C1-C10 alkyl, C1-C10 alkyl substituted with one or more R₁₅, C2-C10alkenyl, C2-C10 alkenyl substituted with one or more R₁₅, C2-C10 alkynyland C2-C10 alkynyl substituted with one or more R₁₅;

Each R₁₇ is independently selected from the group consisting of C1-C10alkyl, C1-C10 alkyl substituted with one or more R₁₅, C2-C10 alkenyl,C2-C10 alkenyl substituted with one or more R₁₅, C2-C10 alkynyl, C2-C10alkynyl substituted with one or more R₁₆, C3-C10 cycloalkyl, C3-C10cycloalkyl substituted with one or more R₁₆, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₁₆, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₁₆, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₁₆, C5-C11bicycloalkyl, C5-C11 bicycloalkyl substituted with one or more R₁₆,C5-C11 bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one ormore R₁₆, 5-11 membered heterobicycloalkyl, 5-11 memberedheterobicycloalkyl substituted with one or more R₁₆, 5-11 memberedheterobicycloalkenyl, 5-11 membered heterobicycloalkenyl substitutedwith one or more R₁₆, halo, OR₁₄, SR₁₄, NR₁₄R₁₄, C(O)OR₁₄, NO₂, CN,C(O)R₁₄, C(O)C(O)R₁₄, C(O)NR₁₄R₁₄, C(O)C(O)NR₁₄R₁₄, N(R₁₄)C(O)R₁₄,NR₁₄S(O)_(t)R₁₄, N(R₁₄)C(O)OR₁₄, NR₁₄C(O)C(O)R₁₄, NR₁₄C(O)NR₁₄R₁₄,NR₁₄S(O)_(t)NR₁₄R₁₄, NR₁₄S(O)_(t)R₁₄, S(O)_(t)R₁₄, S(O)_(t)NR₁₄R₁₄,OC(O)R₁₄, optionally substituted aryl and optionally substitutedheteroaryl; and

t is 1 or 2.

All stereoisomers and double bond geometries are encompassed.

In another embodiment, the invention is a compound having the Formula(III):

In yet another embodiment, the invention is a compound having theFormula (IV):

In a further embodiment, the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compoundrepresented by Formula (I) or a pharmaceutically acceptable saltthereof.

In another embodiment, the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compoundrepresented by Formula (II) or a pharmaceutically acceptable saltthereof.

In yet another embodiment, the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compoundrepresented by Formula (III) or a pharmaceutically acceptable saltthereof.

In another embodiment, the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compoundrepresented by Formula (IV) or a pharmaceutically acceptable saltthereof.

In a further embodiment, the invention is directed to a method oftreating a patient suffering from an inflammatory condition comprisingadministering to the patient a therapeutically effective amount of acompound represented by Formula (I) or a pharmaceutically acceptablesalt thereof.

In a further embodiment, the invention is directed to a method oftreating a patient suffering from an inflammatory condition comprisingadministering to the patient a therapeutically effective amount of acompound represented by Formula (II) or a pharmaceutically acceptablesalt thereof.

In another embodiment, the invention is directed to a method of treatinga patient suffering from an inflammatory condition comprisingadministering to the patient a therapeutically effective amount of acompound represented by Formula (III) or a pharmaceutically acceptablesalt thereof.

In yet another embodiment, the invention is directed to a method oftreating a patient suffering from an inflammatory condition comprisingadministering to the patient a therapeutically effective amount of acompound represented by Formula (IV) or a pharmaceutically acceptablesalt thereof.

In an additional embodiment, the invention is directed to a method oftreating a patient suffering from a CNS disorder comprisingadministering to the patient a therapeutically effective amount of acompound represented by Formula (I).

In another embodiment, the invention is directed to a method of treatinga patient suffering from a CNS disorder comprising administering to thepatient a therapeutically effective amount of a compound represented byFormula (II).

In an additional embodiment, the invention is directed to a method oftreating a patient suffering from a CNS disorder comprisingadministering to the patient a therapeutically effective amount of acompound represented by Formula (III).

In yet another embodiment, the invention is directed to a method oftreating a patient suffering from a CNS disorder comprisingadministering to the patient a therapeutically effective amount of acompound represented by Formula (IV).

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses novel compounds, methods for thepreparation thereof, pharmaceutical compositions and methods for thetreatment of inflammatory disorders and CNS disorders. The compounds andmethods of the invention are particularly useful for treatment ofinflammatory conditions.

In one embodiment, the invention is a compound represented by Formula(I) or a pharmaceutically acceptable salt thereof. The variables ofFormula (I) are as described above.

In another embodiment, the invention is a compound represented by theFormula (Ia):

or a pharmaceutically acceptable salt thereof, wherein A is as definedabove for Formula (I).

In one embodiment, when the compound has the Formula (I) or (Ia), A isR₁.

In another embodiment, when the compound has the Formula (I) or (Ia), Dis independently selected from the group consisting of C1-C10 alkyl,C1-C10 alkyl substituted with one or more R₈, halo, haloalkyl, OR₇, SR₇,NR₇R₇, C(O)OR₇, NO₂ and CN.

In yet another embodiment, when the compound has the Formula (I) or(Ia), k is 0 or 1. In one embodiment, k is 0. In another embodiment, kis 1.

In another embodiment, when the compound has the Formula (I) or (Ia), R₁is selected from the group consisting of:

In one embodiment m is 0. In another embodiment, m is an integer from 1to 6. In a further embodiment, m is an integer from 1 to 3.

In another embodiment, when the compound has the Formula (I) or (Ia), R₁is selected from the group consisting of:

In one embodiment, p is 0. In another embodiment, p is an integer from 1to 3. In an additional embodiment, R₁ is:

In another embodiment, when the compound has the Formula (I) or (Ia), R₁is selected from the group consisting of:

In one embodiment, n is 0. In another embodiment, n is an integer from1-2.

In one embodiment, R₅ is selected from the group consisting of C1-C10alkyl, C1-C10 alkyl substituted with one or more R₈, C2-C10 alkenyl,C2-C10 alkenyl substituted with one or more R₈, C2-C10 alkynyl, C2-C10alkynyl substituted with one or more R₈, C3-C10 cycloalkyl, C3-C10cycloalkyl substituted with one or more R₉, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₉, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₉, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₉,halo, OR₇, SR₇, NR₇R₇, C(O)OR₇, NO₂, CN, C(O)R₇, C(O)C(O)R₇, C(O)NR₇R₇,N(R₇)C(O)R₇, NR₇S(O)_(q)R₇, N(R₇)C(O)OR₇, NR₇C(O)C(O)R₇, NR₇C(O)NR₇R₇,NR₇S(O)_(q)NR₇R₇, NR₇S(O)_(q)R₇, S(O)_(q)R₇, S(O)_(q)NR₇R₇, OC(O)R₇ andaryl.

In another embodiment, R₅ is selected from the group consisting ofC1-C10 alkyl, C1-C10 alkyl substituted with one or more R₈, halo, OR₇,NR₇NR₇, C(O)OR₇, NO₂ and CN. In another embodiment, R₇ is H, C1-C10alkyl and C2-C10 alkenyl. In yet another embodiment, R₈ is halo,haloalkyl, OR₇, NR₇R₇, NO₂ and CN.

In an additional embodiment, R₅ is selected from the group consisting ofhalo, CF₃ and OCF₃.

In another embodiment, when the compound has the Formula (I) or (Ia), R₁is selected from the group consisting of:

In one embodiment, R₆ is selected from the group consisting of C1-C10alkyl, C1-C10 alkyl substituted with one or more R₈, halo, OR₇, NR₇NR₇,C(O)OR₇, NO₂ and CN. In another embodiment, R₇ is H, C1-C10 alkyl andC2-C10 alkenyl. In another embodiment R₈ is halo, haloalkyl, CF₃, OCF₃,OR₇, NR₇R₇, NO₂ and CN.

In a further embodiment, when the compound has the Formula (I) or (Ia),R₁ is:

In one embodiment, R₁₀ is selected from the group consisting of 6membered monocyclic aryl, 5 or 6 membered monocyclic heteroarylcomprising 1-3 heteroatoms, 8-12 membered bicyclic aryl, 8-12 memberedbicyclic heteroaryl comprising 1-6 heteroatoms, 11-14 membered tricyclicaryl and 11-14 membered heteroaryl comprising 1-9 heteroatoms, whereineach of said heteroatoms is independently selected from the groupconsisting of O, N and S and wherein each of the aryl and heteroaryl areoptionally substituted with one or more R₁₁.

In an additional embodiment, R₁₀ is a 6 membered monocyclic aryl whereinthe aryl is optionally substituted with one or more R₁₁.

In yet another embodiment, R₁₀ is:

In yet another embodiment, there is an R₁₁ substitution at the2-position of the phenyl ring. It is to be understood that when there isan R₁₁ substitution at the 2-position of the phenyl ring, there can beadditional R₁₁ substitutions at any available carbon in the phenyl ring.

In one embodiment, R₁₀ is a 5 or 6 membered heteroaryl comprising one ormore heteroatoms, wherein each of said heteroatoms is independentlyselected from O, S and N and wherein the heteroaryl is optionallysubstituted with one or more R₁₁. In a further embodiment, R₉ isthienyl, furyl or pyrrolyl, wherein each of said thienyl, furyl orpyrrolyl is optionally substituted with one or more R₁₁.

In a further embodiment, when the compound has the Formula (I) or (Ia),A is R₂, wherein R₂ is R₃—X—R₄. In one embodiment, R₃ is phenyl orpyridinyl, wherein the phenyl and pyridyl are optionally substitutedwith one or more R₁₁. In yet another embodiment, R₄ is aryl orheteroaryl, wherein each of the aryl or heteroaryl is optionallysubstituted with one or more R₁₁. In a further embodiment, X is O.

In an additional embodiment, R₂ is selected from the group consistingof:

In yet another embodiment, R₄ is:

In yet another embodiment, R₄ is:

wherein Y is selected from the group consisting of CH, CR₁₁ and N; and ris an integer from 0 to 3.

In another embodiment, when the compound has the Formula (I) or (Ia), R₅is selected from the group consisting of C1-C10 alkyl, C1-C₁₀ alkylsubstituted with one or more R₈, C2-C10 alkenyl, C2-C₁₀ alkenylsubstituted with one or more R₈, C2-C₁₀ alkynyl, C2-C10 alkynylsubstituted with one or more R₈, C3-C10 cycloalkyl, C3-C10 cycloalkylsubstituted with one or more R₉, C4-C₁₀ cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₉, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₉, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₉,halo, OR₇, SR₇, NR₇R₇, C(O)OR₇, NO₂, CN, C(O)R₇, C(O)C(O)R₇, C(O)NR₇R₇,N(R₇)C(O)R₇, NR₇S(O)_(q)R₇, N(R₇)C(O)OR₇, NR₇C(O)C(O)R₇, NR₇C(O)NR₇R₇,NR₇S(O)_(q)NR₇R₇, NR₇S(O)_(q)R₇, S(O)_(q)R₇, S(O)_(q)NR₇R₇, OC(O)R₇,aryl and heteroaryl, wherein the aryl and heteroaryl are each optionallysubstituted with one or more R₁₁.

In an additional embodiment, R₅ is selected from the group consisting ofC1-C10 alkyl, C₁-C10 alkyl substituted with one or more R₈, C2-C10alkenyl, C2-C10 alkenyl substituted with one or more R₈, C3-C10cycloalkyl, C3-C10 cycloalkyl substituted with one or more R₉, halo,OR₇, SR₇, NR₇R₇, C(O)OR₇, NO₂, CN, C(O)R₇, C(O)C(O)R₇, C(O)NR₇R₇,N(R₇)C(O)R₇, NR₇S(O)_(q)R₇, N(R₇)C(O)OR₇, NR₇C(O)C(O)R₇, NR₇C(O)NR₇R₇,NR₇S(O)_(q)NR₇R₇, NR₇S(O)_(q)R₇, S(O)_(q)R₇, S(O)_(q)NR₇R₇ and OC(O)R₇.

In another embodiment, R₅ is selected from the group consisting ofC1-C10 alkyl, C1-C10 alkyl substituted with one or more R₈, halo, OR₇,NR₇R₇, SR₇, C(O)OR₇, NO₂ and CN.

In one embodiment, R₇ is H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10cycloalkyl, haloalkyl, aryl and heteroaryl, where said aryl andheteroaryl are each optionally substituted with one or more R₁₁. Inanother embodiment, R₈ is halo, haloalkyl, OR₇, NR₇R₇, C(O)R₇, OC(O)R₇,C(O)OR₇, NO₂ and CN.

In another embodiment, R₇ is H, C1-C10 alkyl, C2-C10 alkenyl andhaloalkyl. In yet another embodiment R₈ is halo, haloalkyl, OR₇, NR₇R₇,SR₇, NO₂ and CN.

In an additional embodiment, R₁₁ is selected from the group consistingof C1-C10 alkyl, C1-C10 alkyl substituted with one or more R₈, C2-C10alkenyl, C2-C10 alkenyl substituted with one or more R₈, C3-C10cycloalkyl, C3-C10 cycloalkyl substituted with one or more R₉, halo,OR₇, SR₇, NR₇R₇, C(O)OR₇, NO₂, CN, C(O)R₇, C(O)C(O)R₇, C(O)NR₇R₇,N(R₇)C(O)R₇, NR₇S(O)_(q)R₇, N(R₇)C(O)OR₇, NR₇C(O)C(O)R₇, NR₇C(O)NR₇R₇,NR₇S(O)_(q)NR₇R₇, NR₇S(O)_(q)R₇, S(O)_(q)R₇, S(O)_(q)NR₇R₇ and OC(O)R₇.

In an additional embodiment, R₁₁ is selected from the group consistingof C1-C10 alkyl, C₁-C10 alkyl substituted with one or more R₈, halo,OR₇, NR₇R₇, SR₇, C(O)OR₇, NO₂ and CN.

In a further embodiment, the invention is a compound of Formula (II) ora pharmaceutically acceptable salt thereof. The variables of Formula(II) are as described above.

In one embodiment, the invention is a compound of the Formula (IIa):

or a pharmaceutically acceptable salt thereof, wherein R₁₂ and R₁₃ areeach as defined above for Formula (II).

In one embodiment, the compound has the Formula (II) or (IIa), R₁₂ is:

In another embodiment, the compound has the Formula (II) or (IIa),wherein R₁₂ is:

In one embodiment, the compound has the Formula (II) or (IIa), whereinR₁₃ is selected from the group consisting of 6 membered monocyclic aryl,5 or 6 membered monocyclic heteroaryl, 8-12 membered bicyclic aryl and8-12 membered bicyclic heteroaryl comprising 1-6 heteroatoms, whereinthe aryl and heteroaryl are each optionally substituted with one or moreR₁₇.

In another embodiment, the compound has the Formula (II) or (IIa),wherein R₁₃ is selected from the group consisting of 6 memberedmonocyclic aryl and 5 or 6 membered monocyclic heteroaryl, wherein thearyl and heteroaryl are each optionally substituted with one or moreR₁₇.

In yet another embodiment, the compound has the Formula (II) or (IIa),wherein R₁₃ is:

wherein u is an integer from 0 to 5.

In a further embodiment, the compound has the Formula (II) or (IIa)wherein R₁₃ is pyridinyl.

In one embodiment, R₁₇ is selected from the group consisting of C1-C10alkyl, C1-C10 alkyl substituted with one or more R₈, C2-C10 alkenyl,C2-C10 alkenyl substituted with one or more R₈, C3-C10 cycloalkyl,C3-C10 cycloalkyl substituted with one or more R₉, halo, OR₇, SR₇,NR₇R₇, C(O)OR₇, NO₂, CN, C(O)R₇, C(O)C(O)R₇, C(O)NR₇R₇, N(R₇)C(O)R₇,NR₇S(O)_(q)R₇, N(R₇)C(O)OR₇, NR₇C(O)C(O)R₇, NR₇C(O)NR₇R₇,NR₇S(O)_(q)NR₇R₇, NR₇S(O)_(q)R₇, S(O)_(q)R₇, S(O)_(q)NR₇R₇ and OC(O)R₇.

In yet another embodiment, R₁₇ is selected from the group consisting ofC1-C10 alkyl, C1-C10 alkyl substituted with one or more R₈, halo, OR₇,NR₇R₇, SR₇, C(O)OR₇, NO₂ and CN.

In another embodiment, the compound has the Formula (V):

In yet another embodiment, the compound has the Formula (VI):

In another embodiment, the compound has the Formula (V) or (VI), whereineach R₁₇ is independently selected from the group consisting of C1-C10alkyl, C1-C10 alkyl substituted with one or more R₁₅, halo, CF₃, OCF₃,OR₁₄, NR₁₄NR₁₄, C(O)OR₁₄, NO₂ and CN. In yet another embodiment, eachR₁₄ is independently selected from the group consisting of H, C1-C10alkyl and C2-C10 alkenyl. In additional embodiment, each R₁₅ isindependently selected from the group consisting of halo, haloalkyl,CF₃, OCF₃, OR₁₄, NR₁₄R₁₄, NO₂ and CN; and u is an integer from 0 to 5.

Representative compounds of the invention include, but are not limitedto, the following:

-   3-(3-(3-(4-chlorophenoxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-(4-phenoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-(3-phenoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   2-(4-((5,6-dihydro-2-(pyridin-3-yl)pyridin-3(4H)-ylidene)methyl)phenoxy)pyrimidine;-   2-(3-((5,6-dihydro-2-(pyridin-3-yl)pyridin-3(4H)-ylidene)methyl)phenoxy)pyrimidine;-   3-(3-(3-(4-methoxyphenoxy)benzylidene)-3,4,5,6-tetrahdyropyridin-2-yl)pyridine;-   3-(3-(3-(4-tert-butoxyphenoxy)benzylidene)-3,4,5,6-tetrahdyropyridin-2-yl)pyridine;-   3-(3-(3,5-dichlorophenoxy)benzylidene)-3,4,5,6-tetrahdyropyridin-2-yl)pyridine;-   3-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)-4H-chromen-4-one;-   3-((5,6-dihydro-2-(pyridin-3-yl)pyridin-3(4H)-ylidene)methyl)-6-nitro-4H-chromen-4-one;-   7-fluro-3-((5,6-dihydro-2-(pyridin-3-yl)pyridin-3(4H)-ylidene)methyl)-6-nitro-4H-chromen-4-one;-   3-((5,6-dihyrdo-2-(pyridin-3-yl)pyridin-3(4H)-ylidene)methyl)-7-methyl-4H-chrome-4-one;-   7-chloro-3-((5,6-dihyrdo-2-(pyridin-3-yl)pyridin-3(4H)-ylidene)methyl)-6-methyl-4H-chromen-4-one;-   3-(3-(biphenyl-4-ylmethylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((9H-fluoren-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2-fluorobiphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((3-fluoro-4′-methoxybiphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((3-fluoro-3′-methoxybiphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((3-fluoro-3    ′-(trifluoromethoxy)biphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-(3-methoxy-4-(m-tolyloxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-(3-methoxy-4-(4-methoxyphenoxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-(2-methoxy-4-(m-tolyloxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   2-phenoxy-5-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)pyridine;-   3-(3-((5-phenylfuran-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(4-chlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(3-chlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(2-chlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(3,4-dichlorophenyl)furan-2-yl)methylene-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-(5-(2,5-dichlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-(5-(3-chloro-4-methoxyphenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3,4,5,6-tetrahydro-3-((5-(2-(trifluormethoxy)phenyl)furan-2-yl)methylene)pyridin-2-yl)pyridine;-   3-(3,4,5,6-tetrahydro-3-((5-(4-(trifluormethoxy)phenyl)furan-2-yl)methylene)pyridin-2-yl)pyridine;-   3-(3-((5-(2-(trifluoromethyl)phenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(2-chloro-5-(trifluoromethyl)phenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(2-chloro-4-(trifluoromethyl)phenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(3,5-bis(trifluoromethyl)phenyl)furan-2-yl)methylene-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(4-fluoro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   4-(5-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)furan-2-yl)benzenesulfonamide    dihydrochloride;-   3-(3-((5-(3-fluoro-2-(trifluoromethyl)phenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine    dihydrochloride-   3-(3,4,5,6-tetrahydro-3-((5-(2-nitrophenyl)furan-2-yl)methylene)pyridin-2-yl)pyridine;-   3-(3,4,5,6-tetrahydro-3-((5-(3-nitrophenyl)furan-2-yl)methylene)pyridin-2-yl)pyridine;-   3-(3-((5-(2,4-dichlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(4-nitrophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(4-chloro-2-nitrophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(2,4-dimethoxyphenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(2-fluoro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(2-fluorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-(4-fluorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-o-tolylfuran-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine    dihydrochloride;-   1-phenyl-3-(4-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)phenyl)urea;-   1-(3,4-dichlorophenyl)-3-(4-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)phenyl)urea;-   1-(3-methoxyphenyl)-3-(4-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)phenyl)urea;-   4-(3-(2-fluoro-4-methoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)isoquinoline;-   4-(3-(2,4-dimethoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)isoquinoline;-   6-(3-(2,4-dimethoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)quinoline;-   6-(3-((5-(2-chlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)quinoline;-   6-(3-(2-fluoro-4-methoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)quinoline;-   6-3,4,5,6-tetrahydro-3-((napthalen-1-yl)methylene)pyridin-2-quinoline;-   3-(3-((2′-fluorobiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-fluorobiphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-methoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-(biphenyl-2-ylmethylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((3′-(trifluoromethyl)biphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((4′-(trifluoromethyl)biphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-fluorobiphenyl-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((3′-methoxybiphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((3′-fluorobiphenyl-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((4′-fluorobiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′,4′-difluorobiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-chlorobiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((3′-chlorobiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-isopropoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-(trifluoromethyl)biphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((3    ′-(trifluoromethyl)biphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((6-fluoro-2′-methoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((6-fluoro-2′-methylbiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-chloro-6-fluorobiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((3    ′-(trifluoromethoxy)biphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′,4′-dimethoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((6-fluorobiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((6-fluoro-3′-methoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((6-fluoro-3′-(trifluoromethoxy)biphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((3′,6-difluorobiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-methylbiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((6-fluoro-2′-(trifluoromethyl)biphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′,6-difluorobiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-(trifluoromethoxy)biphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   N-(2′-fluoro-5′-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)biphenyl-3-yl)acetamide;-   3-(3-((2′,6-difluoro-3′-(trifluoromethyl)biphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((6-fluoro-2′-phenoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((6-methoxy-2′-phenoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-chloro-6-methoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-ethoxy-6-methoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-ethoxy-4-methoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-ethoxy-6′-fluoro-6-methoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-ethoxy-6′-fluoro-4-methoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-(biphenyl-3-ylmethylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-ethoxy-6′-fluorobiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((6-methoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((4′-chlorobiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-fluoro-6-methoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((3′-methoxybiphenyl-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((5-methoxybiphenyl-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′,6-dimethoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((6-methoxy-2′-(trifluoromethyl)biphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((6-methoxy-2′-methylbiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((2′-ethoxybiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;-   3-(3-((6-fluorobiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine;    and-   3-(3-((2′-ethoxy-6-fluorobiphenyl-3-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine.

Compounds were named using ChemDraw Ultra 9.0.1 (CambridgeSoft,Cambridge, Mass.).

The term “alkyl”, as used herein, unless otherwise indicated, refers toboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms; for example, “C1-C10 alkyl”denotes alkyl having 1 to 10 carbon atoms. Examples of alkyl include,but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl,2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.

The term, “alkenyl”, as used herein, refers to both straight andbranched-chain moieties having the specified number of carbon atoms andhaving at least one carbon-carbon double bond.

The term, “alkynyl”, as used herein, refers to both straight andbranched-chain moieties having the specified number or carbon atoms andhaving at least one carbon-carbon triple bond.

The term “cycloalkyl,” as used herein, refers to cyclic alkyl moietieshaving 3 or more carbon atoms. Examples of cycloalkyl include, but arenot limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl.

The term “cycloalkenyl,” as used herein, refers to cyclic alkenylmoieties having 3 or more carbon atoms.

The term “cycloalkynyl,” as used herein, refers to cyclic alkynylmoieties having 5 or more carbon atoms.

The term “heterocycloalkyl” as used herein refers to cycloalkyl groupscontaining one or more heteroatoms (O, S, or N) within the ring.

The term “heterocycloalkenyl” as used herein refers to cycloalkenylgroups containing one or more heteroatoms (O, S or N) within the ring.

The term “bicycloalkyl” as used herein refers to a non-aromaticsaturated carbocyclic group consisting of two rings. Examples ofbicycloalkyl groups include, but are not limited to,bicyclo-[2.2.2]-octyl and norbornyl.

The term “bicycloalkenyl” as used herein refers to bicycloalkyl groupsas defined above, except comprising one or more double bonds connectingcarbon ring members (an “endocyclic double bond”) and/or one or moredouble bonds connecting a carbon ring member and an adjacent non-ringcarbon (an “exocyclic double bond”).

The term “heterobicycloalkyl” as used herein refers to bicycloalkylgroups containing one or more heteroatoms (O, S or N) within a ring.

The term “heterobicycloalkenyl” as used herein refers to bicycloalkenylgroups containing one or more heteroatoms (O, S or N) within a ring.

Cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl,heterocycloalkyl, heterocycloalkyl, heterobicycloalkyl andheterobicycloalkenyl groups also include groups similar to thosedescribed above for each of these respective categories, but which aresubstituted with one or more oxo moieties.

The term “aryl”, as used herein, refers to an aromatic carbocyclicgroup. An aryl group may be substituted or unsubstituted. Examples ofaryl groups include, but are not limited to, phenyl and naphthyl. Eacharyl group is optionally substituted with one or more substituentsenumerated herein, which can be identical or different. A suitablesubstituent on an aryl is any substituent that does not substantiallyinterfere with the pharmaceutical activity of the disclosed compound.Examples of suitable substituents for a substitutable carbon atom in anaryl group include, but are not limited to, C1-C10 alkyl, C1-C10 alkylsubstituted with one or more R₈, C2-C10 alkenyl, C2-C10 alkenylsubstituted with one or more R₈, C2-C10 alkynyl, C2-C10 alkynylsubstituted with one or more R₈, C3-C10 cycloalkyl, C3-C10 cycloalkylsubstituted with one or more R₉, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₉, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₉, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₉, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₉, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₉,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₉, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₉,halo, OR₇, SR₇, NR₇R₇, C(O)OR₇, NO₂, CN, C(O)R₇, C(O)C(O)R₇, C(O)NR₇R₇,N(R₇)C(O)R₇, NR₇S(O)_(q)R₇, N(R₇)(C(O)OR₇), NR₇C(O)C(O)R₇, NR₇C(O)NR₇R₇,NR₇S(O)_(q)NR₇R₇, NR₇S(O)_(q)R₇, S(O)_(q)R₇, S(O)_(q)NR₇R₇, OC(O)R₇,optionally substituted aryl and optionally substituted heteroaryl.

The term “heteroaryl”, as used herein, refers to aromatic carbocyclicgroups containing one or more heteroatoms (O, S, or N) within a ring. Aheteroaryl group can be monocyclic or polycyclic. A heteroaryl group mayadditionally be substituted or unsubstituted. The heteroaryl groups ofthis invention can also include ring systems substituted with one ormore oxo moieties. Examples of heteroaryl groups include, but are notlimited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl,isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl,indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl,oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl,dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl,pyrolopyrimidinyl, and azaindolyl.

The foregoing heteroaryl groups may also be C-attached orheteroatom-attached (where such is possible). For instance, a groupderived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached).

Each heteroaryl group is optionally substituted with one or moresubstituents enumerated herein. A suitable substituent on a heteroarylgroup is one that does not substantially interfere with thepharmaceutical activity of the disclosed compound. A heteroaryl may haveone or more substituents, which can be identical or different. Examplesof suitable substituents for a substitutable carbon atom in a heteroarylgroup include, but are not limited to, C1-C10 alkyl, C1-C10 alkylsubstituted with one or more R₈, C2-C10 alkenyl, C2-C10 alkenylsubstituted with one or more R₈, C2-C10 alkynyl, C2-C10 alkynylsubstituted with one or more R₈, C3-C10 cycloalkyl, C3-C10 cycloalkylsubstituted with one or more R₉, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₉, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₉, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₉, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₉, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₉,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₉, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₉,halo, OR₇, SR₇, NR₇R₇, C(O)OR₇, NO₂, CN, C(O)R₇, C(O)C(O)R₇, C(O)NR₇R₇,N(R₇)C(O)R₇, NR₇S(O)_(q)R₇, N(R₇)(C(O)OR₇), NR₇C(O)C(O)R₇, NR₇C(O)NR₇R₇,NR₇S(O)_(q)NR₇R₇, NR₇S(O)_(q)R₇, S(O)_(q)R₇, S(O)_(q)NR₇R₇, OC(O)R₇,optionally substituted aryl and optionally substituted heteroaryl.

The term “haloalkyl” as used herein refers to an alkyl group having 1 to(2n+1) subsituent(s) independently selected from F, Cl, Br or I, where nis the maximum number of carbon atoms in the alkyl group. Haloalkylincludes, for example, CH₂F, CHF₂ and CF₃.

The term “pyridinyl,” as used herein is meant to encompass 2-pyridinyl,3-pyridinyl and 4-pyridinyl groups. A pyridinyl may be substituted orunsubstituted.

As used herein, a “pharmaceutically acceptable salt” is an ionicbond-containing product of the reaction between the disclosed compoundwith either an acid or a base, suitable for administering to a subject.Pharmaceutically acceptable salts are well known in the art and aredescribed, for example, in Berge et al (1977), Pharmaceutical Salts.Journal of Pharmaceutical Sciences, 69(1): 1-19, the contents of whichare herein incorporated by reference. A non-limiting example of apharmaceutically acceptable salt is an acid salt of a compoundcontaining an amine or other basic group which can be obtained byreacting the compound with a suitable organic or inorganic acid, such ashydrogen chloride, hydrogen bromide, acetic acid, perchloric acid andthe like. Examples of pharmaceutically acceptable salts also can bemetallic salts including, but not limited to, sodium, magnesium,calcium, lithium and aluminum salts. Further examples ofpharmaceutically acceptable salts include sulfates, methanesulfonates,nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g.(+)-tartrates, (−)-tartrates or mixtures thereof including racemicmixtures), succinates, benzoates and salts with amino acids such asglutamic acid. Salts can also be formed with suitable organic bases whenthe compound comprises an acid functional group such as —COOH or —SO₃H.Such bases suitable for the formation of a pharmaceutically acceptablebase addition salts with compounds of the present invention includeorganic bases that are nontoxic and strong enough to react with the acidfunctional group. Such organic bases are well known in the art andinclude amino acids such as arginine and lysine, mono-, di-, andtriethanolamine, choline, mono-, di-, and trialkylamine, such asmethylamine, dimethylamine, and trimethylamine, guanidine,N-benzylphenethylamine, N-methylglucosamine, N-methylpiperazine,morpholine, ethylendiamine, tris(hydroxymethyl)aminomethane and thelike.

In one embodiment, the invention pertains to a pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound disclosed herein. As used herein, a “pharmaceuticalcomposition” is a formulation comprising a compound of the invention ina therapeutically effective amount and a pharmaceutically acceptablediluent or carrier, in a form suitable for administration to a subject.The pharmaceutical composition can be in bulk or in unit dosage form.The unit dosage form can be in any of a variety of forms, including, forexample, a capsule, an IV bag, a tablet, a single pump on an aerosolinhaler, or a vial. The quantity of active ingredient (i.e., aformulation of the disclosed compound or salts thereof) in a unit doseof composition is an effective amount and may be varied according to theparticular treatment involved. It may be appreciated that it may benecessary to make routine variations to the dosage depending on the ageand condition of the patient. The dosage will also depend on the routeof administration. A variety of routes are contemplated, including, butnot limited to, parenteral, oral, pulmonary, ophthalmic, nasal, rectal,vaginal, aural, topical, buccal, transdermal, mucosal, intravenous,intramuscular, subcutaneous, intradermal, intraocular, intracerebral,intracerbroventricular, intralymphatic, intraarticular, intrathecal andintraperitoneal.

The compounds described herein can be used in pharmaceuticalpreparations in combination with a pharmaceutically acceptable carrieror diluent. Suitable pharmaceutically acceptable carriers include inertsolid fillers or diluents and sterile aqueous or organic solutions. Thecompounds will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedherein. Techniques for formulation and administration of the compoundsof the instant invention can be found in Remington: the Science andPractice of Pharmacy, 19^(th) edition, Mack Publishing Co., Easton, Pa.(1995).

In a further embodiment, the invention pertains to the treatment oralleviation of a condition mediated by the α7 nAChR. Conditions that aremediated by the α7 nAChR include, but are not limited to, aninflammatory condition, a CNS disorder, symptoms of nicotine withdrawal,cessation of smoking, treatment of chronic pain and treating a learningor memory impairment. As used herein, the “α7 nAChR,” is a receptorcomprising a α7 subunit. The receptor can comprise only the α7 subunit;alternatively the receptor comprises α7 subunit(s) and other nicotinicreceptor subunit(s). In one embodiment, the receptor is a homopentamerof (α7 subunits. In another embodiment, the receptor of is aheteropentamer of the α7 subunit and other nicotinic receptor subunits.An “α7 subunit” is intended to include all α7 subunit isoforms and/orvariants including, but not limited to, the α7 duplicate nicotinicacetylcholine receptor (“dupα7”) described in Villiger et al., Journalof Immunology 126: 86-98 (2002) and Gault et al., Genomics 52:173-85(1998), the splice variant α7-2 described in US 20040152160 and thepromoter variant(s) of the α7 nicotinic receptor described in U.S. Pat.No. 6,875,606.

In another embodiment, the invention pertains to the treatment of aninflammatory condition in a mammal suffering therefrom comprisingadministering a compound of formula (I). In yet another embodiment, theinvention pertains to the treatment of an inflammatory condition in amammal suffering therefrom comprising administering a compound offormula (II). In a further embodiment, the invention pertains to thetreatment of an inflammatory condition in a mammal suffering therefromcomprising administering a compound of formula (III). In an additionalembodiment, the invention pertains to the treatment of an inflammatorycondition in a mammal suffering therefrom comprising administering acompound of formula (IV). In one embodiment, the inflammatory conditionis selected from the group consisting of appendicitis, peptic, gastricor duodenal ulcers, peritonitis, pancreatitis, pseudomembranous colitis,acute colitis, ulcerative colitis, ischemic colitis, diverticulitis,epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Crohn'sdisease, enteritis, ileus, Whipple's disease, asthma, chronicobstructive pulmonary disease, acute lung injury, allergy, anaphylacticshock, immune complex disease, organ ischemia, reperfusion injury, organnecrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia,hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis,septic abortion, epididymitis, vaginitis, prostatitis, urethritis,bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis,pneumoultramicroscopic silicovolcanoconiosis, alvealitis, bronchiolitis,pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytialvirus, herpes, disseminated bacteremia, Dengue fever, candidiasis,malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis,dermatomyositis, sunburn, urticaria, warts, wheals, vasulitis, angiitis,endocarditis, arteritis, atherosclerosis, thrombophlebitis,pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa,rheumatic fever, Alzheimer's disease, celiac disease, congestive heartfailure, adult respiratory distress syndrome, meningitis, encephalitis,multiple sclerosis, cerebral infarction, cerebral embolism,Guillame-Barre syndrome, neuritis, neuralgia, spinal cord injury,paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis,Paget's disease, gout, periodontal disease, rheumatoid arthritis,synovitis, myasthenia gravis, thryoiditis, systemic lupus erythematosus,Goodpasture's syndrome, Behcet's syndrome, allograft rejection,graft-versus-host disease, Type I diabetes, ankylosing spondylitis,Berger's disease, Type II diabetes, Retier's syndrome and Hodgkinsdisease.

In another embodiment, the inflammatory condition is selected from thegroup consisting of rhinitis, cystic fibrosis, atherosclerosis,congestive heart failure, gout, peritonitis, pancreatitis, ulcerativecolitis, Crohn's disease, asthma, acute lung injury, organ ischemia,reperfusion injury, sepsis, cachexia, bums, myocardial ischemia, adultrespiratory distress syndrome, multiple sclerosis, rheumatoid arthritis,systemic lupus erythematous, chronic obstructive pulmonary disease,psoriasis, Behcet's syndrome, allograft rejection, graft-versus-hostdisease and ileus.

In yet another embodiment, the inflammatory condition is selected fromthe group consisting of peritonitis, pancreatitis, ulcerative colitis,Crohn's disease, asthma, acute lung injury, organ ischemia, reperfusioninjury, sepsis, cachexia, bums, myocardial ischemia, adult respiratorydistress syndrome, multiple sclerosis, rheumatoid arthritis, systemiclupus erythematous, chronic obstructive pulmonary disease, psoriasis,Behcet's syndrome, allograft rejection, graft-versus-host disease andileus.

In a further embodiment, the inflammatory condition is selected from thegroup consisting of peritonitis, pancreatitis, ulcerative colitis,Crohn's disease, asthma, sepsis, adult respiratory distress syndrome,rheumatoid arthritis, systemic lupus erythematosus, chronic obstructivepulmonary disease, psoriasis and ileus.

In a further embodiment, the invention is directed to a method forinhibiting the release of a cytokine from a mammalian cell. As usedherein, a cytokine is a soluble protein or peptide which is naturallyproduced by mammalian cells and which act in vivo as humoral regulatorsat micro- to picomolar concentrations. Cytokines can, either undernormal or pathological conditions, modulate the functional activities ofindividual cells and tissues. A proinflammatory cytokine is a cytokinethat is capable of causing any of the following physiological reactionsassociated with inflammation: vasodialation, hyperemia, increasedpermeability of vessels with associated edema, accumulation ofgranulocytes and mononuclear phagocytes, or deposition of fibrin. Insome cases, the proinflammatory cytokine can also cause apoptosis, suchas chronic heart failure, where tumor necrosis factor alpha (TNF-α) hasbeen shown to stimulate cardiomyocyte apoptosis (Pulkki, 1997; Tsutsuiet al. 2000). Nonlimiting examples of proinflammatory cytokines areTNF-α, interleukin (IL)-1α, IL-1B, IL-6, IL-8, IL-18, interferon-γ(IFN-γ), high mobility group box 1 protein (HMGB1), platelet-activatingfactor (PAF), and macrophage migration inhibitory factor (MIF). In oneembodiment, the invention is directed to a method for inhibiting therelease of a cytokine from a mammalian cell, wherein the cytokine isselected from the group consisting of TNF-α, IL-1α, IL-1β, IL-6, IL-8,IL-18, IFN-γ, HMGB1, PAF and MIF. In yet another embodiment, thecytokine is selected from the group consisting of TNF-γ, HMGB1, IL-1α,IL-1β, IL-6 and IL-18. In an additional embodiment, the cytokine isselected from the group consisting of TNF-α and HMGB1. Any mammaliancell that produces proinflammatory cytokines may be inhibited by thepractice of the disclosed method. Nonlimiting examples are monocytes,macrophages, mast cells, neutrophils, epithelial cells, osteoblasts,fibroblasts, smooth muscle cells, and neurons. In one embodiment of theinvention, the mammalian cell is selected from the group consisting of amonocyte, a macrophage and a neutrophil. In another embodiment, themammalian cell is a macrophage.

In yet another embodiment, the invention is directed to a method for thetreatment of a central nervous system (CNS) disorder in a mammalsuffering therefrom comprising administering a compound of Formula (I)to the mammal. As used herein, the term “CNS disorder,” includesneurological disorders, neuropsychiatric disorders, neurologic diseases,mental illnesses, neurodegenerative diseases, behavioral disorders,cognitive disorders and cognitive affective disorders. A CNS disordercan be drug induced, attributed to genetic predisposition, infection ortrauma or can be of unknown etiology. In one embodiment, the CNSdisorder is selected from the group consisting of dementia, Parkinson'sdisease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania,attention deficit disorder, anxiety, schizophrenia, Tourette's syndrome,manic depression, anxiety, Alzheimer's disease, learning deficit,cognitive deficit, memory loss, autism, amyotrophic lateral sclerosisand neuroendocrine disorders (e.g., obesity, bulemia and diabetesinsipidus). In a further embodiment, the CNS disorder is Alzheimer'sdisease. In a preferred embodiment of the disclosed methods, the mammalis a human.

In a further embodiment, the CNS disorder is pain. The method of theinvention can be used to treat acute, chronic or recurrent painincluding, but not limited to, pain from migraine, postoperative pain,pain from chronic headache, and neuropathic pain.

As used herein, “treatment” and/or “treating” refer to the therapeutictreatment as well as prophylactic treatment or preventative measures. Asused herein, an “effective amount” of a compound of the disclosedinvention is the quantity which, when administered to a subject in needof treatment, improves the prognosis of the subject, e.g., delays orprevents the onset of and/or reduces the severity of one or more of thesubject's symptoms associated with an inflammatory condition and/or aCNS disorder and/or a condition mediated by an α7 receptor. The amountof the disclosed compound to be administered to a subject will depend onthe particular disease or condition, the mode of administration, and thecharacteristics of the subject, such as general health, other diseases,age, sex, genotype, body weight and tolerance to drugs. The skilledartisan will be able to determine appropriate dosages depending on theseand other factors.

The disclosed compounds can be co-administered with one or moreadditional agents such as antibiotics, anti-inflammatory agents (e.g.,ibuprofen, prednisone, corticosteroid, pentofylline), anti-fungals(e.g., Amphotericin B, Fluconazole, Ketoconazol and Itraconazol),steroids, decongestants, bronchodialators, and the like. The disclosedcompounds can also be co-administered with anti-TNF agents, such asinfliximab, etanercept, adalimumab, CDP870, CDP571, Lenercept orThalidomide. The formulation may also contain preserving agents,solubilizing agents, chemical buffers, surfactants, emulsifiers,colorants, odorants and sweetenters. The disclosed compounds may beco-administered with one or more additional agents separately or in thesame formulation.

The excipient included with the compounds of the pharmaceuticalcompositions of the invention is chosen based on the expected route ofadministration of the composition in therapeutic applications. The routeof administration of the composition depends on the condition to betreated. For example, intravenous injection may be preferred fortreatment of a systemic disorder such as endotoxic shock, and oraladministration may be preferred to treat a gastrointestinal disordersuch as a gastric ulcer. The route of administration and the dosage ofthe composition to be administered can be determined by the skilledartisan without undue experimentation in conjunction with standarddose-response studies. Relevant circumstances to be considered in makingthose determinations include the condition or conditions to be treated,the choice of composition to be administered, the age, weight, andresponse of the individual patient, and the severity of the patient'ssymptoms. Thus, depending on the condition, the composition can beadministered orally, parenterally, intranasally, vaginally, rectally,lingually, sublingually, bucally, intrabuccally and transdermally to thepatient.

Accordingly, compositions designed for oral, lingual, sublingual, buccaland intrabuccal administration can be made without undue experimentationby means well known in the art, for example, with an inert diluent orwith an edible carrier. The compositions may be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the pharmaceutical compositions of the present inventionmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like.

Tablets, pills, capsules, troches and the like may also contain binders,excipients, disintegrating agent, lubricants, glidants, sweeteningagents, and flavoring agents. Some examples of binders includemicrocrystalline cellulose, gum tragacanth or gelatin. Examples ofexcipients include starch or lactose. Some examples of disintegratingagents include alginic acid, corn starch and the like. Examples oflubricants include magnesium stearate or potassium stearate. An exampleof a glidant is colloidal silicon dioxide. Some examples of sweeteningagents include sucrose, saccharin and the like. Examples of flavoringagents include peppermint, methyl salicylate, orange flavoring and thelike. Materials used in preparing these various compositions should bepharmaceutically pure and non-toxic in the amounts used.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor, and the like. For vaginal administration, apharmaceutical composition may be presented as pessaries, tampons,creams, gels, pastes, foams, sprays or sponges.

The present invention includes nasally administering to the mammal atherapeutically effective amount of the composition. As used herein,nasally administering or nasal administration includes administering thecomposition to the mucous membranes of the nasal passage or nasal cavityof the patient. As used herein, pharmaceutical compositions for nasaladministration of a composition include therapeutically effectiveamounts of the compound prepared by well-known methods to beadministered, for example, as a nasal spray, nasal drop, suspension,gel, ointment, cream or powder. Administration of the composition mayalso take place using a nasal tampon or nasal sponge.

For topical administration, suitable formulations may includebiocompatible oil, wax, gel, powder, polymer, or other liquid or solidcarriers. Such formulations may be administered by applying directly toaffected tissues, for example, a liquid formulation to treat infectionof conjunctival tissue can be administered dropwise to the subject'seye, or a cream formulation can be administer to a wound site.

The composition of the present invention can be administeredparenterally such as, for example, by intravenous, intramuscular,intrathecal or subcutaneous injection. Parenteral administration can beaccomplished by incorporating a composition of the present inventioninto a solution or suspension. Such solutions or suspensions may alsoinclude sterile diluents such as water for injection, saline solution,fixed oils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents. Parenteral formulations may also includeantibacterial agents such as, for example, benzyl alcohol or methylparabens, antioxidants such as, for example, ascorbic acid or sodiumbisulfite and chelating agents such as EDTA. Buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose may also be added. The parenteralpreparation can be enclosed in ampules, disposable syringes or multipledose vials made of glass or plastic.

Rectal administration includes administering the pharmaceuticalcompositions into the rectum or large intestine. This can beaccomplished using suppositories or enemas. Suppository formulations caneasily be made by methods known in the art. For example, suppositoryformulations can be prepared by heating glycerin to about 120° C.,dissolving the pharmaceutical composition in the glycerin, mixing theheated glycerin after which purified water may be added, and pouring thehot mixture into a suppository mold.

Transdermal administration includes percutaneous absorption of thecomposition through the skin. Transdermal formulations include patches,ointments, creams, gels, salves and the like.

In addition to the usual meaning of administering the formulationsdescribed herein to any part, tissue or organ whose primary function isgas exchange with the external environment, for purposes of the presentinvention, “pulmonary” will also mean to include a tissue or cavity thatis contingent to the respiratory tract, in particular, the sinuses. Forpulmonary administration, an aerosol formulation containing the activeagent, a manual pump spray, nebulizer or pressurized metered-doseinhaler as well as dry powder formulations are contemplated. Suitableformulations of this type can also include other agents, such asantistatic agents, to maintain the disclosed compounds as effectiveaerosols.

A drug delivery device for delivering aerosols comprises a suitableaerosol canister with a metering valve containing a pharmaceuticalaerosol formulation as described and an actuator housing adapted to holdthe canister and allow for drug delivery. The canister in the drugdelivery device has a head space representing greater than about 15% ofthe total volume of the canister. Often, the compound intended forpulmonary administration is dissolved, suspended or emulsified in amixture of a solvent, surfactant and propellant. The mixture ismaintained under pressure in a canister that has been sealed with ametering valve.

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of cell culture, molecular biology,microbiology, cell biology, and immunology, which are well within theskill of the art. Such techniques are fully explained in the literature.See, e.g., Sambrook et al., 1989, “Molecular Cloning: A LaboratoryManual”, Cold Spring Harbor Laboratory Press; Ausubel et al. (1995),“Short Protocols in Molecular Biology”, John Wiley and Sons; Methods inEnzymology (several volumes); Methods in Cell Biology (several volumes),and Methods in Molecular Biology (several volumes).

Embodiments of the invention are illustrated by the following exampleswhich are not intended to be limiting in any way.

Exemplification

General Experimental Methods

Air and moisture sensitive liquids and reagents were transferred viasyringe and were introduced into glassware under a positive pressure ofdry nitrogen through rubber septa. All reactions were stirredmagnetically. Commercial reagents and solvents were used without furtherpurification. Unless otherwise stated, the term “concentrated underreduced pressure” refers to the use of a Büichi rotary evaporator at10-500 mbar. All temperatures are reported uncorrected in degreesCelsius (° C.). Thin-layer chromatography (TLC) was performed on EMScience pre-coated glass-backed silica gel 60 Å F-254 μm plates.Visualization of the plates was effected by one or more of the followingtechniques: (a) ultraviolet illumination, (b) exposure to iodine vapor,(c) immersion of the plate in a 10% solution of phosphomolybdic acid inethanol followed by heating, (d) immersion of the plate in a ceriumsulfate solution followed by heating, (e) immersion of the plate in anacidic ethanol solution of 2,4-dinitrophenylhydrazine followed byheating and/or (f) immersion of the plate in an acidic ethanol solutionof anisaldehyde followed by heating. Column chromatography was performedon an Argonaut FlashMaster Personal or FlashMaster Personal⁺ Systemusing ISOLUTE Flash Si II silica gel pre-packed cartridges.

High performance liquid chromatography-electrospray mass spectra (LC-MS)were obtained using an Agilent 1100 Series HPLC equipped with a binarypump, a diode array detector monitored at 254 nm and 214 nm, an AgilentZorbax Eclipse XDB-C8 (4.6 mm I.D.×150 mm, 5 micron) column, and anAgilent 1100 Series LC/MSD mass spectrometer with electrosprayionization. Spectra were scanned from 100-1000 amu. The eluant was amixture of H₂O (A) and MeCN (B) containing 0.1% AcOH. A typical gradientwas:

Time Flow (min.) % A % B (mL/min.) 0.00 90 10 1 9.00 10 90 1 9.50 90 101 12.00 90 10 1

Routine one-dimensional NMR spectroscopy was performed on a Varian 400MHz spectrometer at 293 K. The samples were dissolved in deuteratedsolvents obtained from Cambridge Isotope Labs (Andover, Mass.). Thechemical shifts were recorded on the ppm scale and were referenced tothe appropriate residual solvent signal, such as 2.50 ppm for DMSO-d₆,1.93 ppm for CD₃CN, 3.30 for CD₃OD, 5.32 ppm for CD₂Cl₂, and 7.26 ppmfor CDCl₃ for ¹H NMR spectra, and 39.5 ppm for DMSO-d₆, 1.3 ppm forCD₃CN, 49.0 for CD₃OD, 53.8 ppm for CD₂Cl₂, and 77.0 ppm for CDCl₃ for¹³C NMR spectra.

Abbreviations and Acronyms

When the following abbreviations are used throughout the disclosure,they have the following meanings:

-   Ac acetyl-   AcOH or HOAc acetic acid-   aq aqueous-   Boc t-butoxycarbonyl-   Bu butyl-   ¹³C Carbon -13-   Cbz benzyloxycarbonyl-   CDCl₃ deuterochloroform-   CD₂Cl₂ deuteromethylene chloride-   CD₃CN deuteroacetonitrile-   CD₃OD dueteromethanol-   Celite® registered trademark of Celite Corp. brand of diatomaceous    earth-   Cs₂CO₃ cesium carbonate-   Cu(I)CN copper(I) cyanide-   Cu(I)I copper(I) iodide-   d doublet-   dd doublet of doublet-   DIAD diisopropyl azodicarboxylate-   DIEA diisopropylethylamine-   DMAP 4-(N,N-dimethyl)amino pyridine-   DME dimethoxyethane-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DMSO-d₆ dimethylsulfoxide-d₆-   dppf 1,1′-bis(diphenylphosphino)ferrocene-   dt doublet of triplet-   EI electron impact ionization-   EI-MS electron impact—mass spectrometry-   eq equivalent-   Et ethyl-   EtOH ethanol-   Et₂O diethyl ether-   EtOAc ethyl acetate-   g gram(s)-   h hour(s)-   ¹H proton-   ¹H NMR proton nuclear magnetic resonance-   HCl hydrochloric acid-   [HCl] concentrated hydrochloric acid-   Hex hexanes-   HNEt₂ diethylamine-   HPLC high performance liquid chromatography-   [H₂SO₄] concentrated sulfuric acid-   Hz hertz-   iPrOH isopropanol-   K degrees Kelvin-   LC-MS liquid chromatography—mass spectrometry-   LDA lithium diisopropylamide-   m multiplet-   M molar-   m/z mass over charge-   [M+H]⁺ mass of the molecular ion+hydrogen-   Me methyl-   MeOH methanol-   MeCN acetonitrile-   mg milligram(s)-   MHz megahertz-   min minute(s)-   mL milliliter(s)-   mol mole(s)-   mmol millimole(s)-   MS mass spectrometry-   MtBE methyl tert-butyl ether-   N normal-   N₂ nitrogen gas-   NMR nuclear magnetic resonance-   Na₂CO₃ sodium carbonate-   NaH sodium hydride-   NaHCO₃ sodium hydrogen carbonate or sodium bicarbonate-   NaOAc sodium acetate-   NaOH sodium hydroxide-   Na₂SO₄ sodium sulfate-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   NMP N-methyl-2-pyrrolidone-   Pd/C palladium on carbon-   PdCl₂(dppf)-CH₂Cl₂    [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex    with dichloromethane (1:1)-   Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)-   Ph phenyl-   PPh₃ triphenylphosphine-   ppm parts per million-   psi pounds per square inch-   Pr propyl-   q quartet-   qt quintet-   quant. quantitative-   R_(f) TLC retention factor-   rt room temperature-   RT HPLC retention time-   s singlet-   TBS tert-butyldimethylsilyl-   TBSCl tert-butyldimethylsilyl chloride-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   THMD 2,2,6,6-tetramethyl-3,5-heptadione-   ° C. degrees Celsius-   Δ reflux

EXAMPLE 1 Synthesis of3-(3-(3-(4-chlorophenoxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

3-(5-Ammoniopentanoyl)pyridinium chloride (162 mg, 0.64 mmol) wassuspended in a reaction vessel with i-propanol (12 mL).3-(4-chlorophenoxy)benzaldehyde (225 mg, 0.97 mmol) was then added andthe reaction vessel sealed. The reaction was heated to 80° C. overnightand then cooled to room temperature. The precipitate was recovered byvacuum filtration, washed with a 20% i-propanol in hexane solution thendried under vacuum giving 161 mg (56%) of a tan-colored solid. LC-MS:RT=6.22 min, [M+H]⁺=375.1.

The compounds shown in Table 1 were prepared by similar methods asdescribed for Example 1, substituting the appropriate aldehyde. Thecompounds below were isolated as dihydrochloride salts unless otherwisenoted.

TABLE 1

LC MS Example R_(a) R_(b) R_(c) Yield RT [M + H]⁺ 2 H

H 41% 5.78 min 341.0 3

H H 77% 5.85 min 341.1 4 H

H 65% 3.89 min 343.1 5

H H 78% 4.02 min 343.1 6

H H 71% 5.72 min 371.1 7

H H 51% 7.18 min 397.2 8

H H 44% 6.84 min 409.1 9

H H 49% 5.85 min 343.0 10 H

H 52% 5.89 min 343.0 11

H H 42% 5.54 min 355.6 12 H H Ph 81% 5.28 325.5 min 13

H H 53% 6.19 min 393.6 14

H H 60% 6.17 min 393.6 15 H H

53% 5.37 min 343.5 16 H

H 57% 5.51 min 355.6 17 H H

44% 5.39 min 343.5 18

H H 54% 5.62 min 343.5 19

H H 70% 5.81 min 361.6

EXAMPLE 20 Synthesis of3-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)-4H-chromen-4-onedihydrochloride

3-(5-Ammoniopentanoyl)pyridinium chloride (219 mg, 0.87 mmol) and3-formylchromone (228 mg, 1.31 mmol) were combined and suspended in areaction vessel with i-propanol (30 mL). The reaction vessel was sealedand the reaction heated to 85 ° C. overnight then cooled to roomtemperature. The precipitate was recovered by vacuum filtration, washedwith a 20% i-propanol in hexane solution, then dried under vacuum giving245 mg (72%) of a powdery brown solid. LC-MS: RT=4.20 min, [M+H]⁺=317.1.

The compounds shown in Table 2 were prepared as described in Example 9,substituting the appropriate reactant. The compounds below were isolatedas dihydrochloride salts unless otherwise noted.

TABLE 2

Example R_(c) R_(d) Yield LC RT MS [M + H]⁺ 21 —NO₂ —H 90% 4.41 min362.1 22 —F —H 90% 4.32 min 335.1 23 —CH₃ —H 68% 4.53 min 331.1 24 —Cl—CH₃ 60% 5.19 min 365.0

EXAMPLE 25 Synthesis of3-(3-(biphenyl-4-ylmethylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

3-(5-Ammoniopentanoyl)pyridinium chloride (128 mg, 0.51 mmol) wassuspended in methanol (2 mL) and treated with N,N-diisopropylethylamine(165 mg, 1.27 mmol) in a reaction vessel. This gave a clear solution. Adual solution of 0.6 M acetic acid and 0.3 M sodium acetate in methanol(10 mL) was then added, followed by addition of 4-phenylbenzaldehyde(140 mg, 0.76 mmol). The reaction vessel was then sealed and thereaction heated to 80 ° C. overnight then cooled to room temperature.The reaction mixture was then concentrated under reduced pressure,treated with a saturated solution of NaHCO_(3(aq)), and extracted threetimes with EtOAc. The EtOAc extracts were washed with brine, thencombined, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The recovered material was eluted through a 20 gram column ofsilica gel with 7:7:7:1:0.1 hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH eluant. Onesample was recovered and dried under vacuum. This sample was thendissolved into MeOH and treated with two equivalents of 6 N HCl_((aq)),concentrated under reduced pressure and re-crystallized from isopropanolgiving 80 mg (39%) of yellow needles. LC-MS: RT=5.72 min, [M+H]⁺ =325.1.

EXAMPLE 26 Synthesis of3-(3-((9H-fluoren-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

3-(5-Ammoniopentanoyl)pyridinium chloride (122 mg, 0.48 mmol) wassuspended in methanol (2 mL) and treated with N,N-diisopropylethylamine(157 mg, 1.21 mmol) in a reaction vessel. This gave a clear solution. Adual solution of 0.6 M acetic acid and 0.3 M sodium acetate in methanol(10 mL) was then added, followed by addition offluorine-2-carboxaldehyde (140 mg, 0.72 mmol). The reaction vessel wasthen sealed and the reaction heated to 80° C. overnight, then cooled toroom temperature. The reaction mixture was partially concentrated underreduced pressure, treated with a saturated solution of NaHCO₃ (aq), andextracted three times with EtOAc. The EtOAc extracts were washed withbrine, then combined, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The recovered material was eluted through a 20 gramcolumn of silica gel with 7:7:7:1:0.1 hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH (430mL), then with 96:4:0.4 CH₂Cl₂:MeOH:NH₄OH (250 mL). One sample wasrecovered and dried under vacuum. This sample was then dissolved intoMeOH and treated with two equivalents of 6 N HCl_((aq)), concentratedunder reduced pressure and re-crystallized from isopropanol giving 42 mg(21%) of orange crystals. LC-MS: RT =5.70 min, [M+H]⁺=337.0.

EXAMPLE 27 Synthesis of3-(3-((2-fluorobiphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

3-(5-Ammoniopentanoyl)pyridinium chloride (150 mg, 0.60 mmol) and2-fluorobiphenyl-4-carboxaldehyde (155 mg, 0.78 mmol) were combined in areaction vessel and treated with ethanol (10 mL) and concentratedHCl_((aq)) (5 drops). The vessel was then sealed and the reaction washeated to 85° C. overnight then cooled to room temperature. The reactionmixture was then concentrated under reduced pressure then partiallydissolved into hot isopropanol. This mixture was left to cool andcrystals formed. The crystals were recovered by vacuum filtration,washed with fresh isopropanol, and dried under vacuum giving 92 mg (36%)of a yellow solid. LC-MS: RT=5.88 min, [M+H]⁺=343.1.

EXAMPLE 28 Synthesis of3-(3-((3-fluoro-4′-methoxybiphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

The synthesis of3-(3-((3-fluoro-4′-methoxybiphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride is depicted below.

A. Step 1. Preparation of Intermediate 1

3-(5-Ammoniopentanoyl)pyridinium chloride (104 mg, 0.41 mmol) wassuspended in ethanol (10 mL) in a reaction vessel. Five drops ofconcentrated hydrochloric acid was added, followed by the addition of3-fluoro-4-formylphenylboronic acid (76 mg, 0.46 mmol). The reactionvessel was sealed, and the reaction was heated to 85 ° C. with stirringovernight. The reaction was then cooled to room temperature andconcentrated under reduced pressure. The recovered material was thenimmediately taken on to the next second step without furtherpurification.

B. Step 2. Preparation of3-(3-((3-fluoro-4′-methoxybiphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

Intermediate 1 was dissolved into a mixture of toluene (10 mL), methanol(2 mL), and dioxane (2 mL). The 2 M Na₂CO_(3(aq)) solution (2.0 mL, 4mmol) was then added, followed by the addition of the 4-bromoanisole(230 mg, 1.23 mmol) and thedichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct catalyst (29 mg, 0.04 mmol). The reaction vesselwas then flushed with nitrogen and sealed. The reaction was then heatedto 80° C. with stirring overnight. The reaction was then cooled to roomtemperature and quenched with saturated NH₄Cl_((aq)) and extracted threetimes with EtOAc. The EtOAc extracts were then washed with brine,combined, dried over Na₂SO₄, filtered and concentrated under reducedpressure. This gave a black oil that was eluted through a 20 gram columnof silica gel with 7:7:7:1:0.1 hexane: MtBE:CH₂Cl₂:MeOH:NH₄OH (660 mL).One sample was recovered that was dissolved into isopropanol and treatedwith 2 equivalents of 6 N HCl_((aq)). This solution was then dilutedwith ether which caused a precipitate to form. This precipitate wasrecovered by vacuum filtration, washed with ether and dried under vacuumgiving 81 mg (44%) of a brown solid. LC-MS: RT=5.90 min, [M+H]⁺=373.1.

EXAMPLE 29 Synthesis of3-(3-((3-fluoro-3′-methoxybiphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

The preparation of3-(3-((3-fluoro-3′-methoxybiphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride is shown below.

A. Step 1: Preparation of Intermediate 2

3-(5-Ammoniopentanoyl)pyridinium chloride (307 mg, 1.22 mmol) and4-bromo-2-fluorobenzaldehyde (619 mg, 3.05 mmol) were combined in areaction vessel and treated with ethanol (24 mL) and concentratedhydrochloric acid (5 drops). The reaction vessel was sealed and thereaction was heated to 85° C. with stirring. When no further reactionwas observed by HPLC/MS, the reaction was cooled to room temperature andconcentrated under reduced pressure. The recovered material was treatedwith a saturated solution of NaHCO_(3(aq)), and extracted three timeswith EtOAc. The EtOAc extracts were washed with brine, then combined,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Therecovered material was eluted through a 20 gram column of silica gelwith 98:2:0.2 CH₂Cl₂:MeOH:NH₄OH (1 liter). One sample was recovered anddried under vacuum. This sample was then re-crystallized fromisopropanol giving 81 mg (19%) of white needles. LC-MS: RT=5.33 min,[M+H]⁺=347.0. The mother liquor from the crystallization contained 144mg (34%) of the mass balance as a clear brown film. The material fromthe mother liquor was taken on to the second step.

B. Step 2: Preparation of3-(3-((3-fluoro-3′-methoxybiphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

Intermediate 2 (144 mg, 0.42 mmol) was dissolved into toluene (12 mL)and dioxane (2.5 mL) in a reaction vessel. 3-Methoxybenzeneboronic acid(127 mg, 0.84 mmol) and the 2 M Na₂CO_(3(aq)) solution (2.1 mL, 4.2mmol) were added, followed by addition ofdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct catalyst (31 mg, 0.04 mmol). The reaction vesselwas then flushed with nitrogen and sealed. The reaction was then heatedto 85° C. with stirring overnight. The reaction was then cooled to roomtemperature and quenched with water and extracted three times withEtOAc. The EtOAc extracts were then washed with brine, combined, driedover Na₂SO₄, filtered and concentrated under reduced pressure, andeluted through a 20 gram column of silica gel with 99:1:0.1 CH₂Cl₂:MeOH:NH₄OH (1 liter). One sample was recovered that was dissolved intomethanol and treated with 2 equivalents of 6 N HCl_((aq)). This solutionwas then concentrated under reduced pressure and the recovered materialdissolved into hot isopropanol to recrystallize. The crystals formedwere recovered by vacuum filtration, washed with a 10% isopropanol inhexane solution, then dried under vacuum giving 91 mg (48%) of a brownsolid. LC-MS: RT=6.03 min, [M+H]⁺=373.1.

EXAMPLE 30 Synthesis of3-(3-((3-fluoro-3′-(trifluoromethoxy)biphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

3-(3-((3-fluoro-3′-(trifluoromethoxy)biphenyl-4-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride was prepared from Intermediate 2 using the appropriateboronic acid as described for Example 18 giving 50 mg (23%) of a yellowsolid. LC-MS: RT=6.99 min, [M+H]⁺=427.1.

EXAMPLE 31 Synthesis of3-(3-(3-methoxy-4-(m-tolyloxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

The preparation of3-(3-(3-methoxy-4-(m-tolyloxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride is described below.

A. Step 1: Preparation of Intermediate 3

3-(5-Ammoniopentanoyl)pyridinium chloride (518 mg, 2.1 mmol) andvanillin (471 mg, 3.1 mmol) were combined in a reaction vessel andtreated with isopropanol (50 mL). The reaction vessel was sealed and thereaction was heated to 80° C. with stirring overnight. The reaction wasthen cooled to room temperature and the precipitate recovered by vacuumfiltration and washed with a 20% solution of isopropanol in hexane. Therecovered solid was then dried under vacuum giving 740 mg (95%) of ayellow solid. LC-MS: RT=3.70 min, [M+H]⁺=295.1.

B. Step 2. Preparation of3-(3-(3-methoxy-4-(m-tolyloxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

3-(3-(3-methoxy-4-(m-tolyloxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride was prepared as described in Buck et al. Org. Lett.,2002, (4), 9, 1623-1626.

Briefly, Intermediate 3 (60 mg, 0.16 mmol), copper (I) iodide (15 mg,0.08 mmol), cesium carbonate (169 mg, 0.48 mmol) and 3-bromotoluene (112mg, 0.64 mmol) were combined in a reaction vessel and treated with NMP(2 mL). 2,2,6,6-Tetramethyl-3,5-heptadione (29 mg, 0.16 mmol) was thenadded. The reaction vessel was then flushed with nitrogen gas andsealed, and the reaction was heated to 100° C. with stirring for twodays. The reaction was then cooled to room temperature and quenched withconcentrated ammonium hydroxide. This mixture was then extracted threetimes with EtOAc. The EtOAc extracts were washed with brine, combined,dried over Na₂SO₄, filtered and concentrated under reduced pressure.This gave a black oil that was eluted through a 20 gram column of silicagel with CH₂Cl₂ (100 mL) and then with 10.5:7:7:1:0.1hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH (800 mL). One sample was recovered thatwas dissolved into methanol and treated with 2 equivalents of 6 NHCl_((aq)). This solution was concentrated under reduced pressure, andthe recovered material re-crystallized from a mix of isopropanol andether. The crystals were recovered by vacuum filtration, washed with 20%isopropanol in hexane, then dried under vacuum giving 32 mg (38%) of ayellow solid. LC-MS: RT=5.88 min, [M+H]⁺=385.1.

EXAMPLE 32 Synthesis of3-(3-(3-methoxy-4-(4-methoxyphenoxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

Intermediate 3 (80 mg, 0.22 mmol), copper (I) iodide (excess), cesiumcarbonate (233 mg, 0.66 mmol), 2,2,6,6-tetramethyl-3,5-heptadione (88mg, 0.48 mmol) and p-bromoanisole (82 mg, 0.44 mmol) were combined inNMP (5 mL) under nitrogen in a reaction vessel. The reaction vessel wassealed and the reaction was heated to 110° C. with stirring for threedays. The reaction was then cooled to room temperature and quenched withsaturated NH₄Cl_((aq)) and saturated NaHCO_(3(aq)). This mixture wasthen extracted three times with EtOAc. The EtOAc extracts were washedwith brine, combined, dried over Na₂SO₄, filtered and concentrated underreduced pressure. This gave a black oil that was eluted through a 20gram column of silica gel with CH₂Cl₂ (100 mL) and then with10.5:7:7:1:0.1 (510 mL) and then with 7:7:7:1:0.1 (440mL)hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH (step gradient). Two impure samples wererecovered. The purer sample as determined by HPLC/MS was dissolved intoMeOH and treated with two equivalents of 6 N HCl_((aq)), thenconcentrated under reduced pressure. The recovered material wasdissolved into hot isopropanol, cooled to room temperature then treatedwith ether until a precipitate formed. This precipitate was recovered byvacuum filtration, washed with fresh ether, then dried under vacuumgiving 6 mg (5.7%) of a yellow solid. LC-MS: RT=5.59 min, [M+H]⁺=401.0.

EXAMPLE 33 Synthesis of3-(3-(2-methoxy-4-(m-tolyloxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

The preparation of3-(3-(2-methoxy-4-(m-tolyloxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride is described below.

A. Step I. Preparation of Intermediate 4

3-(5-Ammoniopentanoyl)pyridinium chloride (2.53 g, 10.1 mmol) and4-hydroxy-2-methoxybenzaldehyde (2.14 g, 14.1 mmol) were combined in areaction vessel and treated with isopropanol (50 mL). The reactionvessel was sealed and the reaction was heated to 80 ° C. with stirringovernight. The reaction was then cooled to room temperature and treatedwith ether (75 mL). The precipitate that formed was recovered by vacuumfiltration and washed with a 20% solution of isopropanol in hexane andthen with ether. The recovered solid was then dried under vacuum giving3.58 g (96%) of a yellow solid. LC-MS: RT=3.87 min, [M+H]⁺=295.1.

B. Step 2. Preparation of3-(3-(2-methoxy-4-(m-tolyloxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride.

3-(3-(2-methoxy-4-(m-tolyloxy)benzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride was prepared as described in Buck et al. (2002).Briefly, Intermediate 4 (103 mg, 0.28 mmol), copper (I) iodide (27 mg,0.14 mmol), and cesium carbonate (296 mg, 0.84 mmol) were combined in areaction vessel and treated with NMP (2 mL) under nitrogen.3-Bromotoluene (96 mg, 0.56 mmol) and 2,2,6,6-tetramethyl-3,5-heptadione(52 mg, 0.28 mmol) were added. The reaction vessel was sealed, and thereaction was heated to 100° C. with stirring for two days. The reactionwas then cooled to room temperature and quenched with concentratedammonium hydroxide (5 mL) and vigorous stirring for 30 minutes. Thismixture was then extracted three times with EtOAc. The EtOAc extractswere washed with brine, combined, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The recovered material was elutedthrough a 20 gram column of silica gel with 10.5:7:7:1:0.1 (660 mL) andwith 7:7:7:1:0.1 (330 mL) hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH (step gradient).One sample was recovered that was dissolved into methanol and treatedwith 2 equivalents of 6 N HCl_((aq)). This solution was concentratedunder reduced pressure, and the recovered material re-crystallized fromhot isopropanol. The crystals were recovered by vacuum filtration,washed with 20% isopropanol in hexane and then with ether, then driedunder vacuum giving 78 mg (60%) of a yellow solid. LC-MS: RT=6.07 min,[M+H]⁺=385.2.

EXAMPLE 34 Synthesis of2-phenoxy-5-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)pyridinedihydrochloride

3-(5-Ammoniopentanoyl)pyridinium chloride (101 mg, 0.40 mmol) and6-phenoxynicotinaldehyde (120 mg, 0.60 mmol) were combined in a reactionvessel and treated with isopropanol (15 mL). The reaction vessel wassealed and the reaction was heated to 80° C. with stirring overnight.The reaction was then cooled to room temperature. The precipitate thatformed was recovered by vacuum filtration and washed with a 20% solutionof isopropanol in hexane and then with ether. The recovered solid wasthen dried under vacuum giving 122 mg (73%) of a pale yellow solid.LC-MS: RT=5.08 min, [M+H]⁺=342.1.

EXAMPLE 35 Synthesis of3-(3-((5-phenylfuran-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

3-(5-Ammoniopentanoyl)pyridinium chloride (188 mg, 0.75 mmol) wastransferred to a reaction vessel and treated with isopropanol (12 mL).5-Phenyl-2-furaldehyde (193 mg, 1.12 mmol) was added, the reactionvessel was sealed, and the reaction was heated to 85° C. with stirringfor 6 hours. The reaction was then cooled to room temperature, and theprecipitate was recovered by vacuum filtration, washed with isopropanoland ether then dried under vacuum giving 264 mg (91%) of an orangesolid. LC-MS: RT=5.15 min, [M+H]⁺=315.1.

The compounds shown in Table 3 were prepared as described in Example 24using an appropriate aldehyde. The compounds below were isolated asdihydrochloride salts unless otherwise noted.

TABLE 3

MS Example R_(e) R_(f) R_(g) R_(h) Yield LC RT [M + H]⁺ 36 —H —H —Cl —H86% 5.60 349.1 min. 37 —H —Cl —H —H 94% 5.62 349.1 min. 38 —Cl —H —H —H93% 5.60 349.1 min. 39 —H —Cl —Cl —H 85% 6.07 383.0 min. 40 —Cl —H —H—Cl 83% 6.05 383.0 min. 41 —H —Cl —OCH₃ —H 94% 5.59 379.1 min. 42 —OCF₃—H —H —H 81% 5.99 399.1 min. 43 —H —H —OCF₃ —H 85% 6.04 399.1 min. 44—CF₃ —H —H —H 76% 5.81 383.1 min. 45 —H —CF₃ —H —H 86% 6.04 383.1 min.46 —Cl —H —H —CF₃ 47% 6.29 417.0 min. 47 —Cl —H —CF₃ —H 73% 6.60 417.0min. 48 —H —CF₃ —H —CF₃ 72% 6.67 451.0 min. 49 —H —CF₃ —F —H 79% 6.05401.0 min. 50 —H —H —SO₂NH₂ —H 90% 4.18 394.0 min. 51 —NO₂ —H —H —H 62%5.00 360.0 min. 52 —H —NO₂ —H —H 89% 5.29 360.0 min.

EXAMPLE 53 Synthesis of3-(3-((5-(2,4-dichlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine

3-(5-Ammoniopentanoyl)pyridinium chloride (103 mg, 0.41 mmol) and5-(2,4-dichlorophenyl)furfural (128 mg, 0.53 mmol) were combined in areaction vessel and treated with isopropanol (6 mL). The reaction vesselwas sealed and the reaction was heated to 80° C. with stirringovernight. The reaction was then cooled to room temperature,concentrated under reduced pressure and treated with saturatedNaHCO_(3(aq)). This mixture was then extracted three times with EtOAc.The EtOAc extracts were washed with brine, combined, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The recovered materialwas eluted through a 20 gram column of silica gel with 10.5:7:7:0.5:0.05(700 mL) and with 7:7:7:1:0.1 (440 mL) hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH(step gradient). One sample was recovered that slowly solidified. Thissolid material was re-crystallized from a mixture of hot isopropanol andhexane. The crystals were recovered by vacuum filtration, washed with20% isopropanol in hexane and then with ether, then dried under vacuumgiving 71 mg (45%) of a yellow crystalline solid. LC-MS: RT=6.17 min,[M+H]⁺=383.0.

EXAMPLE 54 Synthesis of3-(3-((5-(4-nitrophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine

3-(5-Ammoniopentanoyl)pyridinium chloride (95 mg, 0.38 mmol) and5-(4-nitrophenyl)furfural (99 mg, 0.46 mmol) were combined in a reactionvessel and treated with isopropanol (6 mL). The reaction vessel wassealed and the reaction was heated to 80° C. with stirring overnight.The reaction was then cooled to room temperature, concentrated underreduced pressure and treated with saturated NaHCO_(3(aq)). This mixturewas then extracted three times with EtOAc. The EtOAc extracts werewashed with brine, combined, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The recovered material was elutedthrough a 20 gram column of silica gel with 10.5:7:7:1:0.1hexane:MTBE:CH₂Cl₂:MeOH:NH₄OH (1 liter). One sample was recovered thatappeared to be highly crystalline. This material was re-crystallizedfrom hot methanol. The crystals were recovered by vacuum filtration,washed with isopropanol then dried under vacuum giving 50 mg (36%) of anorange crystalline solid. LC-MS: RT=5.16 min, [M+H]⁺=360.0.

EXAMPLE 55 Synthesis of3-(3-((5-(4-chloro-2-nitrophenyl)furan-2-yl)methylene)-3.4.5.6-tetrahydropyridin-2-yl)pyridinedihydrochloride

3-(5-Ammoniopentanoyl)pyridinium chloride (109 mg, 0.43 mmol) and5-(4-chloro-2-nitrophenyl)furfural (131 mg, 0.52 mmol) were combined ina reaction vessel and treated with isopropanol (6 mL). The reactionvessel was sealed and the reaction was heated to 80° C. with stirringovernight. The reaction was then cooled to room temperature,concentrated under reduced pressure and treated with saturatedNaHCO_(3(aq)). This mixture was then extracted three times with EtOAc.The EtOAc extracts were washed with brine, combined, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The recovered materialwas eluted through a 20 gram column of silica gel with 10.5:7:7:1:0.1hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH (800 mL). One sample was recovered. Thismaterial was dissolved into methanol and treated with 2 equivalents of 6N HCl_((aq)). This solution was concentrated under reduced pressure andthe recovered material re-crystallized from a mix of isopropanol andether. The crystals were recovered by vacuum filtration, washed with a20% solution of isopropanol in hexane, and then with ether, then driedunder vacuum giving 95 mg (47%) of a yellow solid. LC-MS: RT=5.65 min,[M+H]⁺=394.0.

EXAMPLE 56 Synthesis of3-(3-((5-(2,4-dimethoxyphenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

The preparation of3-(3-((5-(2,4-dimethoxyphenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride is described below.

A. Step 1: Preparation of Intermediate 5

3-(5-Ammoniopentanoyl)pyridinium chloride (937 mg, 3.73 mmol) and5-formyl-2-furanboronic acid (522 mg, 3.73 mmol) were combined in areaction vessel and treated with isopropanol (30 mL). The reactionvessel was sealed and the reaction was heated to 80° C. with stirringovernight. The reaction was then cooled to room temperature, treatedwith saturated NaHCO_(3(aq)) and extracted three times with EtOAc. TheEtOAc extracts were washed with brine, then combined, dried over NaSO₄,filtered and concentrated under reduced pressure and dried under vacuumgiving 860 mg of a yellow solid. LC-MS: RT=2.68 min, [M+H]⁺=283.0.

B. Step 2: Preparation of3-(3-((5-(2,4-dimethoxyphenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine

Intermediate 5 (95 mg, 0.33 mmol), 2,4-dimethoxybromobenzene (143 mg,0.66 mmol), and Pd(PPh₃)₄ (38 mg, 0.03 mmol) were combined in a reactionvessel and treated with a 1:1 mixture of toluene (5 mL) and 1,4-dioxane(5 mL). 2 M Na₂CO_(3(aq)) (330 μL, 0.66 mmol) was then added and thereaction vessel flushed with N₂ and sealed. The reaction mixture wasthen heated to 110° C. with stirring overnight. The reaction was thencooled to room temperature and treated with EtOAc. This solution wasthen washed with water and brine. The aqueous extracts were then backextracted two times with fresh EtOAc. All EtOAc extracts were thencombined, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The recovered material was then eluted through a 20 gramcolumn of silica gel with 99:1:0.1 CH₂Cl₂:MeOH:NH₄OH (1.5 liters). Therecovered material was then dissolved into MeOH and treated with 2 eq.of 6 N HCl (aq). This solution was then concentrated under reducedpressure and the recovered material re-crystallized from a mixture ofhot ethanol and isopropanol. The crystals were recovered by vacuumfiltration and washed with a 20% solution of isopropanol in hexane, andthen with ether, then dried under vacuum giving 22 mg (14%) of redcrystals. LC-MS: RT=5.59 min, [M+H]⁺=375.0.

EXAMPLE 57 Synthesis of3-(3-((5-(2-fluoro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

Intermediate 5 (190 mg, 0.67 mmol) was dissolved into a 1:1 mixture oftoluene (10 mL) and 1,4-dioxane (10 mL) in a reaction vessel.2-Fluoro-3-(trifluoromethyl)bromobenzene (326 mg, 1.34 mmol), Pd(PPh₃)₄(81 mg, 0.07 mmol), and 2 M Na₂CO_(3(aq)) (670 μL, 1.34 mmol) were thenadded and the reaction vessel flushed with N₂ and sealed. The reactionmixture was then heated to 110° C. with stirring for two days. Thereaction was then cooled to room temperature, filtered through celite,and the filtrate concentrated under reduced pressure. The recoveredmaterial was then treated with water and extracted three times withEtOAc. The EtOAc extracts were then washed with brine, combined, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Therecovered material was then eluted through a 20 gram column of silicagel with 98:2:0.2 CH₂Cl₂:MeOH:NH₄OH (1 liter). The recovered materialwas then dissolved into MeOH and treated with 2 eq. of 6 N HCl_((aq)).This solution was then concentrated under reduced pressure and therecovered material re-crystallized from a mixture of hot ethanol andisopropanol. The crystals were recovered by vacuum filtration and washedwith a 20% solution of isopropanol in hexane, and then with ether, thendried under vacuum giving 30 mg (9.5%) of orange crystals. LC-MS:RT=6.17 min, [M+H]⁺=401.0.

EXAMPLE 58 Synthesis of3-(3-((5-(2-fluorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride.

Intermediate 5 (95 mg, 0.33 mmol), 1-fluoro-2-bromobenzene (118 mg, 0.66mmol), and Pd(PPh₃)₄ (38 mg, 0.03 mmol) were combined in a reactionvessel and treated with a 1:1 mixture of toluene (5 mL) and 1,4-dioxane(5 mL). 2 M Na₂CO_(3(aq)) (330 μL, 0.66 mmol) was added, along with MeOH91 mL. The reaction vessel was then flushed with N₂ and sealed and thereaction mixture heated to 110° C. with stirring overnight. The reactionwas then cooled to room temperature, filtered through celite. Thefiltrate was then treated with water and extracted three times withEtOAc. The EtOAc extracts were then washed with brine, combined, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Therecovered material was then eluted through a 20 gram column of silicagel with 99:1:0.1 CH₂C₂:MeOH:NH₄OH (1 liter). The material recoveredfrom this column was then eluted through an Agilent 1100 SeriesPreparative HPLC system with an Agilent Prep-C18 (21.2 mm I.D.×150 mm)column equipped with an Agilent Prep-C18 (21.2 mm I.D.) guard column,and the following continuous gradient mobile phase using was a mixtureof H₂O (A) and MeCN (B) containing 0.1% TFA:

Time Flow (min.) % A % B (mL/min.) 0.00 90 10 30 1.00 90 10 30 11.00 1090 30 14.00 10 90 30 15.00 90 10 30 16.00 90 10 30

The recovered material was then dissolved into MeOH and treated with 2eq. of 6 N HCl_((aq)). This solution was then concentrated under reducedpressure and the recovered material dissolved into isopropanol. Anorange precipitate was crashed out of this solution with ether, thenrecovered by vacuum filtration and washed with fresh ether, then driedunder vacuum giving 22 mg (16%) of an orange solid. LC-MS: RT=5.42 min,[M+H]⁺=333.0.

EXAMPLE 59 Synthesis of3-(3-((5-(4-fluorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

The preparation of3-(3-((5-(4-fluorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride is described below.

A. Step 1: Preparation of Intermediate 6

3-(5-Ammoniopentanoyl)pyridinium chloride (5.86 g, 23.3 mmol) wastreated with saturated NaHCO_(3(aq)) and extracted three times withEtOAc. The EtOAc extracts were washed with brine, combined, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The recoveredmaterial was eluted through a 50 gram column of silica gel with10.5:7:7:1:0.1 hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH (1 liter). One sample wasrecovered giving 485 mg (13%, 3.03 mmol) of a light brown oil. This oilwas dissolved into a dual solution of 0.6 M acetic acid and 0.3 M sodiumacetate in methanol (30 mL) in a reaction vessel. 5-Bromo-2-furaldehyde(795 mg, 4.54 mmol) was added, the reaction vessel was sealed, and thereaction was heated to 65° C. with stirring for 24 hours. The reactionwas then cooled, concentrated under reduced pressure, and treated with asaturated solution of NaHCO_(3(aq)) and extracted three times withEtOAc. The EtOAc extracts were then washed with brine, combined, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Therecovered material was then eluted through a 20 gram column of silicagel with 98:2:0.2 CH₂Cl₂:MeOH:NH₄OH (1 liter). The recovered materialwas then dried under vacuum giving 220 mg (22%) of a brown oil. LC-MS:RT=4.50 min, [M+H]⁺=318.9.

B. Step 2. Preparation of of3-(3-((5-(4-fluorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

Intermediate 6 (110 mg, 0.34 mmol) was dissolved into toluene (10 mL) ina reaction vessel. 4-Fluorobenzeneboronic acid (95 mg, 0.68 mmol),Pd(PPh₃)₄ (39 mg, 0.03 mmol), and 2 M Na₂CO_(3(aq)) (340 μL, 0.68 mmol)were then added. The reaction vessel was flushed with N₂ and sealed. Thereaction was then heated to 110° C. with stirring overnight. Thereaction was then cooled to room temperature, diluted with EtOAc andwashed with water and with brine. The aqueous extracts were backextracted two times with fresh EtOAc. All EtOAc extracts were combined,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The recovered material was then eluted through a 20 gram column ofsilica gel with 98:2:0.2 CH₂Cl₂:MeOH:NH₄OH (750 mL). The recoveredmaterial was then dissolved into MeOH and treated with 2 eq. of 6 NHCl_((aq)), and concentrated under reduced pressure. The recoveredmaterial was then recrystallized from a mix of hot isopropanol andethanol. The crystals were recovered by vacuum filtration, washed with a20% isopropanol in hexane solution, then with ether, then dried undervacuum giving 73 mg (52%) of yellow needles. LC-MS: RT=5.44 min,[M+H]⁺=333.0.

EXAMPLE 60 Synthesis of3-(3-((5-o-tolylfuran-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

Intermediate 6 (110 mg, 0.34 mmol) was dissolved into toluene (10 mL) ina reaction vessel. 2-Methylbenzeneboronic acid (92 mg, 0.68 mmol),Pd(PPh₃)₄ (39 mg, 0.03 mmol), and 2 M Na₂CO_(3(aq)) (340 μL, 0.68 mmol)were then added. The reaction vessel was flushed with N₂ and sealed. Thereaction was then heated to 110° C. with stirring overnight. Thereaction was then cooled to room temperature, diluted with EtOAc andwashed with water and with brine. The aqueous extracts were backextracted two times with fresh EtOAc. All EtOAc extracts were combined,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The recovered material was then eluted through a 20 gram column ofsilica gel with 98:2:0.2 CH₂Cl₂:MeOH:NH₄OH. The recovered material wasthen dissolved into MeOH and treated with 2 eq. of 6 N HCl_((aq)), andconcentrated under reduced pressure. The recovered material was thenrecrystallized from a mix of hot isopropanol and ethanol. The crystalswere recovered by vacuum filtration, washed with a 20% isopropanol inhexane solution, then with ether, then dried under vacuum giving 73 mg(53%) of orange needles. LC-MS: RT=5.68 min, [M+H]⁺=329.0.

EXAMPLE 61 Synthesis of1-phenyl-3-(4-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)phenyl)ureadihydrochloride

The preparation of1-phenyl-3-(4-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)phenyl)ureadihydrochloride is described below.

A. Step 1: Preparation of Intermediate 7

3-(5-Ammoniopentanoyl)pyridinium chloride (257 mg, 1.02 mmol) and4-acetamidobenzaldehyde (250 mg, 1.53 mmol) were combined in a reactionvessel and treated with ispropanol (20 mL). The reaction vessel wassealed and the reaction was heated to 85° C. overnight. The reaction wascooled to room temperature and treated with ether (50 mL). This produceda yellow precipitate that was recovered by vacuum filtration. Theprecipitate was then washed with a 10% isopropanol in hexane solutionand dried under vacuum giving 360 mg (93%) of a yellow solid. LC-MS:RT=3.55 min, [M+H]⁺=306.1.

B. Step 2: Preparation of Intermediate 8

Intermediate 7 (78 mg, 0.21 mmol) was dissolved into 1 N HCl_((aq)) (2mL, 2 mmol) in a reaction vessel. The reaction vessel was then sealedand the reaction heated to 100° C. overnight. The reaction mixture wasthen cooled to room temperature and treated with 1 N NaOH(aq) untilpH=12. This produced a cloudy yellow precipitate. This mixture was thenextracted 3 times with EtOAc. The EtOAc extracts were washed with brine,combined, dried over Na₂SO₄, filtered, concentrated under reducedpressure, then dried under vacuum giving 51 mg (92%) of a yellow film.LC-MS: RT=3.74 min, [M+H]⁺=264.1.

C. Step 3: Preparation of1-phenyl-3-(4-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)phenyl)ureadihydrochloride

Intermediate 8 (51 mg, 0.19 mmol) was dissolved into CH₂Cl₂ (10 mL)under N₂ at room temperatue. Phenylisocyanate (35 mg, 0.29 mmol) wasthen added and the reaction was stirred at room temperature for 48hours. The reaction was then concentrated under reduced pressure andeluted through a 20 gram column of silica gel with 8.5:7:7:1:0.1hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH (470 mL). One sample was recovered thatwas dissolved into MeOH and treated with 2 eq. of 6 N HCl_((aq)). Thissolution was concentrated under reduced pressure, then partiallydissolved into hot isopropanol. A solid was recovered by vacuumfiltration from this mixture after the solvent had cooled. The recoveredsolid was washed with ether, then dried under vacuum giving 22 mg (23%)of a red powdery solid. LC-MS: RT=5.02 min, [M+H]⁺=383.1.

EXAMPLE 62 Synthesis of1-(3,4-dichlorophenyl)-3-(4-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)phenyl)ureahydrochloride

Intermediate 8 (118 mg, 0.45 mmol), Cs₂CO₃ (317 mg, 0.90 mmol), and3,4-dichlorophenylisocyanate (126 mg, 0.67 mmol) were combined under N₂and treated with CH₂Cl₂ (10 mL). This mixture was then vigorouslystirred for 5 days. The reaction mixture was then directly applied to a20 gram column of silica gel and eluted with a 99:1:0.1 (1 liter) and a95:5:0.5 (250 mL) CH₂Cl₂:MeOH:NH₄OH step gradient. One sample wasrecovered that was dissolved into MeOH and treated with 1 eq. of 6 NHCl_((aq)). This solution was then concentrated under reduced pressureand the recovered material was dissolved into hot isopropanol. When thissolution had cooled, it was diluted with ether, which produced aprecipitate that was recovered by vacuum filtration. This precipitatewas then washed with a 20% isopropanol in hexane solution, then driedunder vacuum giving 51 mg (23%) of a yellow solid. LC-MS: RT=5.97 min,[M+H]⁺=453.1.

EXAMPLE 63 Synthesis of1-(3-methoxyphenyl)-3-(4-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)phenyl)ureahydrochloride

Intermediate 8 (75 mg, 0.28 mmol) and K₂CO₃ (77 mg, 0.56 mmol) werecombined under N₂ and treated with CH₂Cl₂ (10 mL).3-Methoxyphenylisocyanate (84 mg, 0.56 mmol) was then added, and thismixture was vigorously stirred overnight. The reaction mixture was thendirectly applied to a 20 gram column of silica gel and eluted with a99:1:0.1 (1 liter) and a 97.5:2.5:0.25 (500 mL) CH₂Cl₂:MeOH:NH₄OH stepgradient. One sample was recovered that was dissolved into MeOH andtreated with 1 eq. of 6 N HCl_((aq)). This solution was thenconcentrated under reduced pressure and the recovered material wasre-crystallized from a mixture of isopropanol and ether. This solid wasthen recovered by vacuum filtration and washed with a 20% isopropanol inhexane solution and then with ether, then dried under vacuum giving 89mg (70%) of a yellow solid. LC-MS: RT=4.97 min, [M+H]⁺=413.2.

EXAMPLE 64 Synthesis of4-(3-(2-fluoro-4-methoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)isoquinolinedihydrochloride

The preparation of4-(3-(2-fluoro-4-methoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)isoquinolinedihydrochloride is described below.

A. Step 1. Preparation of Intermediate 9

Intermediate 9 was prepared as described in Tyson, F. T. J. Am. Chem.Soc., 1939, 61 (1), 183-185. Briefly, 4-Bromoisoquinoline (3.36 g, 16.2mmol) and Cu(I)CN (2.17 g, 24.2 mmol) were combined as the dry solids ina round bottom flask fitted with a magnetic stirrer and vigeraux columnunder N₂. Heat was applied. At approximately 150° C., the mixture beganto stir freely. At approximately 230° C., the reaction mixture formed ablack solid that began to splatter onto the sides of the flask. Thereaction was cooled to room temperature and treated with concentratedNH₄OH overnight. This mixture was then extracted 3 times with EtOAc. TheEtOAc extracts were washed with dilute NH₄OH_((aq)) and brine, thencombined, dried over Na₂SO₄, treated with decolorizing charcoal,filtered through celite, then concentrated under reduced pressure. Therecovered material was dissolved into a mixture of hot isopropanol andmethanol to re-crystallize. The crystals were recovered by vacuumfiltration, washed with fresh isopropanol and dried under vacuum giving1.47 g (58%) of yellow crystals. LC-MS: RT=7.86 min, [M+H]⁺=155.1.

B. Step 2. Preparation of Intermediate 10

Intermediate 10 was prepared as described in Tyson et al. Briefly,Intermediate 9 (1.47g, 9.5 mmol) was transferred to a reaction vesseland treated with concentrated hydrochloric acid (12 mL). The reactionvessel was sealed and the reaction mixture was heated to 150° C. withstirring for 8 hours, then cooled to room temperature. This gave a whitesolid that was recovered by vacuum filtration, washed with isopropanol,and dried under vacuum giving 1.74 g (87%) of a white crystalline solid.LC-MS: RT=3.64 min, [M+H]⁺=174.1.

C. Step 3: Preparation of Intermediate 11

Intermediate 10 (1.47 g, 7.0 mmol) was suspended into CH₂Cl₂ (100 mL)under N₂ at room temperature and treated with N,N-diisopropylethylamine(1.0 g, 7.7 mmol). Dimethylformamide (catalytic, 4 drops) was added,followed by the addition of the oxalyl chloride (1.02 g, 8.0 mmol).There was a gas evolution and the reaction mixture developed an opaqueyellow color. This mixture was stirred at room temperature for 45minutes then cooled to 0° C. and treated with additional 1.1 eq. ofN,N-diisopropylethylamine (1.0 g, 7.7 mmol). An excess of methanol (5mL) was then added, and the reaction mixture was left to stir overnightwith gradual warming to room temperature. The reaction was then treatedwith saturated NaHCO_(3(aq)) and extracted three times with CH₂Cl₂. TheCH₂Cl₂ extracts were washed with brine, combined, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The recoveredmaterial was then eluted through a 50 gram column of silica gel with a10% (750 mL) and 20% (500 mL) EtOAc: hexane step gradient. One samplewas recovered and dried under vacuum giving 1.17 g (89%) of an off whitesolid. LC-MS: RT=8.25 min, [M+H]⁺=188.1.

D. Step 4: Preparation of Intermediate 12

Intermediate 12 was prepared as described in U.S. Pat. No. 5,602,257 toZoltewicz. δ-Valerolactam (4.67 g, 47.1 mmol), formaldehyde (37% by wt.in H₂O, 4.6 mL of solution, 1.70 g, 56.5 mmol), and diethylamine (4.13g, 56.5 mmol) were combined in a reaction vessel. The reaction vesselwas flushed with N₂, then sealed and the reaction mixture was heated to80° C. overnight. The reaction was then cooled to room temperature,partially concentrated under reduced pressure, then extracted threetimes with EtOAc. The EtOAc extracts were then washed with brine,combined, dried over Na₂SO₄, filtered, concentrated under reducedpressure and dried under vacuum giving 6.49 g (74%) of a yellow mobileoil. ¹H NMR (DMSO-d6) δ 4.05 (s, 2 H), 3.26 (broad m, 2 H), 2.48 (q, 4H, J=7.2 Hz), 2.21 (broad m, 2 H), 1.68 (broad m, 4 H), 0.94 (t, 6 H,J=7.2 Hz).

E. Step 5: Preparation of Intermediate 13

Intermediate 11 (1.35 g, 7.2 mmol) and Intermediate 12 (1.39 g, 7.6mmol) were combined and dissolved into toluene (50 mL) under N₂ at roomtemperature. NaH (346 mg, 14.4 mmol) was added, and the reaction mixturewas heated to reflux with stirring, under N₂, overnight. An additional 2eq. of NaH (346 mg, 14.4 mmol) was then added, and reflux was continuedfor 3.5 hours. The reaction was then cooled to room temperature andfiltered under vacuum. The filtrate was then concentrated under reducedpressure. The recovered material was then treated with concentratedhydrochloric acid (25 mL) and acetone (5 mL) and heated to refluxovernight. The reaction was then cooled to room temperature, dilutedwith isopropanol (150 mL) and cooled to −20 ° C. Crystals did form andwere recovered by vacuum filtration, washed with fresh isopropanol, anddried under vacuum giving 371 mg (17%) of a white solid. LC-MS: RT=5.45min, [M+H]⁺=229.1.

F. Step 6: Preparation of4-(3-(2-fluoro-4-methoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)isoquinolinedihydrochloride

Intermediate 13 (133 mg, 0.44 mmol) was suspended into methanol (2 mL)in a reaction vessel and treated with N,N-diisopropylethylamine (143 mg,1.10 mmol). This gave a solution. 2-Fluoro-4-methoxybenzaldehyde wasthen added. This solution was then treated with a dual solution of 0.6 MHOAc and 0.3 M NaOAc in methanol (10 mL). The reaction vessel was sealedand the reaction heated to 80° C. for 24 hours, then cooled to roomtemperature. The reaction mixture was then partially concentrated underreduced pressure and the recovered material treated with saturatedNaHCO_(3(aq)). This mixture was then extracted three times with EtOAc.The EtOAc extracts were then washed with brine, combined, dried overNa₂SO₄, filtered, concentrated under reduced pressure. The recoveredmaterial was then eluted through a 20 gram column of silica gel with7:7:7:1:0.1 hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH (660 mL). One sample wasrecovered that was dissolved into MeOH and treated with 2 eq. of 6 NHCl_((aq)). This solution was then concentrated under reduced pressureand the recovered material was re-crystallized from hot isopropanol.This solid was then recovered by vacuum filtration and washed with freshisopropanol, then dried under vacuum giving 85 mg (46%) of yellowneedles. LC-MS: RT=5.20 min, [M+H]⁺=346.9.

EXAMPLE 65 Synthesis of 4-(3-(2,4-dimethoxybenzylidene)-3,4,56-tetrahydropyridin-2-yl)isoquinoline sulfate

Intermediate 13 (134 mg, 0.44 mmol) was dissolved into a dual solutionof 0.6 M HOAc and 0.3 M NaOAc in methanol (10 mL) in a reaction vessel.2,4-Dimethoxybenzaldehyde (148 mg, 0.88 mmol) was then added and thereaction vessel sealed. The reaction was then heated to 80° C. withstirring overnight, then cooled to room temperature. The reactionmixture was then partially concentrated under reduced pressure and therecovered material treated with saturated NaHCO_(3(aq)). This mixturewas extracted three times with EtOAc. The EtOAc extracts were thenwashed with brine, combined, dried over Na₂SO₄, filtered, concentratedunder reduced pressure. The recovered material was then eluted through a20 gram column of silica gel with 99:1:0.1 CH₂Cl₂:MeOH:NH₄OH (1 liter).One sample was recovered that was dissolved into MeOH and treated with 1eq. of a 1 N H₂SO_(4(aq)) solution, then concentrated under reducedpressure. The recovered material was then dissolved into hot isopropanoland precipitated from solution with ether. The precipitate was recoveredby vacuum filtration, washed with ether, then dried under vacuum giving3 mg (1.5%) of a yellow solid. LC-MS: RT=5.23 min, [M+H]⁺=359.0.

EXAMPLE 66 Synthesis of6-(3-(2,4-dimethoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)quinolinehydrochloride

The preparation of6-(3-(2,4-dimethoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)quinolinehydrochloride is described below.

A. Step 1: Preparation of Intermediate 14

Intermediate 14 was prepared as described in EP 0381375 B1, page 21.6-quinolinecarboxylic acid (12.2 g, 70.4 mmol) was suspended intoethanol (70 mL) in a reaction vessel. Concentrated sulfuric acid (12 mL)was added, the reaction vessel was sealed and the reaction was heated to80° C. for 48 hours. The reaction was then cooled to room temperature,partially concentrated under reduced pressure and treated withconcentrated ammonium hydroxide and 1 N NaOH_((aq)) until pH=9. Thisproduced an oil that separated from solution. This mixture was extractedthree times with EtOAc. The EtOAc extracts were then washed with brine,combined, dried over Na₂SO₄, filtered, concentrated under reducedpressure giving a green oil. This oil was filtered through a 9.5 cm×3.0cm plug of silica gel with 50% EtOAc:hexane. The filtrate wasconcentrated under reduced pressure and dried under vacuum giving 10.66g (75%) of a light green oil. ¹H NMR (DMSO-d6) δ 9.03 (dd, 1H, J=4.27,1.70 Hz), 8.70 (d, 1H, J=1.71 Hz), 8.60 (broad d, 1H, J=8.12 Hz), 8.22(dd, 1H, J=8.54, 1.71 Hz), 8.11 (d, 1H, J=8.97 Hz), 7.64 (dd, 1H,J=8.12, 4.27 Hz), 4.40 (q, 2H, J=7.26 Hz), 1.38 (t, 3H, J=7.26 Hz).

B. Step 2: Preparation of Intermediate 15

Intermediate 14 (2.93 g, 14.6 mmol) was dissolved into toluene (100 mL)under N₂ at room temperature. Intermediate 12 (2.68 g, 14.6 mmol) wasadded, followed by the addition of the NaH (701 mg, 29.2 mmol). Therewas a gas evolution. This mixture was heated to reflux for 4 hours underN₂, then partially cooled. A second 2 eq. of NaH (701 mg, 29.2 mmol) wasthen added and the reaction heated to reflux for 4 hours, then graduallycooled to room temperature, with stirring under N₂ overnight. Thereaction mixture was then filtered through celite with toluene, and thefiltrate concentrated under reduced pressure. The recovered material wasthen treated with concentrated hydrochloric acid (50 mL) and acetone (10mL). This mixture was then heated to reflux with stirring overnight. Thereaction mixture was then cooled to room temperature. An oil appeared toform in the reaction mixture. This mixture was treated with concentratedammonium hydroxide until it was basic. The mixture was then extractedthree times with EtOAc. The EtOAc extracts were then washed with brine,combined, dried over Na₂SO₄, filtered, concentrated under reducedpressure giving 880 mg (28%) of a brown oil. ¹H NMR (DMSO-d6) δ 8.90(dd, 1 H, J=3.84, 1.71 Hz), 8.43 (dd, 1 H, J=8.54, 1.10Hz), 8.34 (d, 1H, J=2.14 Hz), 8.30 (dd, 1 H, J=8.97, 2.14Hz), 7.98 (d, 1 H, J=8.97 Hz),7.55 (dd, 1 H, J=8.54, 4.27 Hz), 3.81 (m, 2 H), 2.76 (m, 2 H), 1.65(broad m, 4 H).

C. Step 3. Preparation of6-(3-(2,4-dimethoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)quinolinehydrochloride

Intermediate 15 (214 mg, 1.02 mmol) was dissolved into isopropanol (6mL) in a reaction vessel and treated with 6 N HCl_((aq)) (340 μL, 2.0mmol). 2,4-Dimethoxybenzaldehyde (254 mg, 1.53 mmol) was then added, thereaction vessel was sealed, and the reaction was heated to 85° C. withstirring overnight. The reaction was cooled to room temperature,partially concentrated under reduced pressure, treated with saturatedNaHCO_(3(aq)), then extracted three times with EtOAc. The EtOAc extractswere then washed with brine, combined, dried over Na₂SO₄, filtered,concentrated under reduced pressure. The recovered material was thenpurified by eluting it through 3 successive 20 gram columns of silicagel with the following sequential eluants:

1.) 7:7:7:1:0.1 Hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH.

2.) 99:1:0.1 CH₂Cl₂:MeOH:NH₄OH.

3.) 10.5:7:7:0.5:0.05 Hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH.

This eventually gave a colorless film that was dissolved into MeOH andtreated with 1 eq. of 6 N HCl_((aq)). This solution was thenconcentrated under reduced pressure and the recovered material dissolvedinto isopropanol and precipitated from solution with ether. Theprecipitate was then collected by vacuum filtration, washed with freshether, then dried under vacuum giving 4 mg (1%) of a yellow solid.LC-MS: RT=5.06 min, [M+H]⁺=359.1.

EXAMPLE 67 Synthesis of6-(3-((5-(2-chlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)quinolinehydrochloride

Intermediate 15 (188 mg, 0.89 mmol) was dissolved into isopropanol (20mL) in a reaction vessel and treated with 6 N HCl_((aq)) (300 μL, 1.8mmol). 5-(2-Chlorophenyl)furfural (257 mg, 1.25 mmol) was then added,the reaction vessel was sealed, and the reaction was heated to 85° C.with stirring overnight. The reaction was cooled to room temperature,partially concentrated under reduced pressure, treated with saturatedNaHCO_(3(aq)), then extracted three times with EtOAc. The EtOAc extractswere then washed with brine, combined, dried over Na₂SO₄, filtered,concentrated under reduced pressure. The recovered material was theneluted through a 20 gram column of silica gel with 10.5:7:7:0.5:0.05Hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH (1 liter). The recovered material wasdissolved into MeOH and treated with 1 eq. of 6 N HCl_((aq)). Thissolution was then concentrated under reduced pressure and the recoveredmaterial dissolved into a mixture of isopropanol and ether. Crystalsformed upon cooling, and were recovered by vacuum filtration and washedwith a 20% solution of isopropanol in hexane. The crystals were driedunder vacuum giving 56 mg (14%) of dark brown crystals. LC-MS: RT=5.88min, [M+H]⁺=399.1.

EXAMPLE 68 Synthesis of 6-(3-(2-fluoro-4-methoxybenzylidene)-3,4,56-tetrahydropyridin-2-yl)quinoline dihydrochloride

Intermediate 15 (200 mg, 0.95 mmol) and 2-fluoro-4-methoxybenzaldehyde(220 mg, 1.43 mmol) were combined and dissolved into isopropanol (10 mL)in a reaction vessel, then treated with 6 N HCl_((aq)) (633 μL, 3.8mmol). The reaction vessel was sealed, and the reaction was heated to80° C. with stirring overnight. The reaction was cooled to roomtemperature, concentrated under reduced pressure, treated with saturatedNaHCO₃(aq), then extracted three times with EtOAc. The EtOAc extractswere then washed with brine, combined, dried over Na₂SO₄, filtered,concentrated under reduced pressure. The recovered material was theneluted through a 20 gram column of silica gel with 10.5:7:7:0.5:0.05Hexane: MtBE:CH₂Cl₂:MeOH:NH₄OH (1 liter). The recovered material wasdissolved into MeOH and treated with 2 eq. of 6 N HCl_((aq)). Thissolution was then concentrated under reduced pressure and the recoveredmaterial dissolved into isopropanol and precipitated from solution withether. The precipitate was recovered by vacuum filtration, washed withfresh ether, then dried under vacuum giving 10 mg (2.5%) of a yellowsolid. LC-MS: RT=5.08 min, [M+H]⁺=347.0.

EXAMPLE 69 Synthesis of3-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)pyridinetrihydrochloride

3-(5-Ammoniopentanoyl)pyridinium chloride (152 mg, 0.60 mmol) wassuspended into ethanol (10 mL) in a reaction vessel and treated withconcentrated hydrochloric acid (5 drops). Pyridine-3-carboxaldehyde (84mg, 0.78 mmol) was added and the reaction vessel was sealed. Thereaction was heated to 85° C. for 48 hours, then cooled to roomtemperature. The reaction mixture was concentrated under reducedpressure and treated with saturated NaHCO_(3(aq)), then extracted threetimes with EtOAc. The EtOAc extracts were washed with brine, combined,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The recovered material was then eluted through a 20 gram column ofsilica gel with a 98:2:0.2 and 96:4:0.4 CH₂Cl₂:MeOH:NH₄OH step gradient(500 mL each step). The recovered material was dissolved into MeOH andtreated with 3 eq. of 6 N HCl_((aq)). This solution was concentratedunder reduced pressure and the recovered material dissolved into hotisopropanol. This solution was allowed to cool to room temperature, thendiluted with ether which produced a precipitate. The precipitate wasrecovered by vacuum filtration, washed with fresh isopropanol, thendried under vacuum giving 39 mg (18%) of a brown solid. LC-MS: RT=2.14min, [M+H]⁺=250.1.

EXAMPLE 70 Synthesis of methyl3-(5-((2-(pyridin-3-yl)-5,6-dihydropyridin-3(4H)-ylidene)methyl)furan-2-yl)thiophene-2-carboxylatedihydrochloride

3-(5-Ammoniopentanoyl)pyridinium chloride (99 mg, 0.39 mmol) and methyl3-(5-formyl-2-furyl)thiophene-2-carboxylate (102 mg, 0.43 mmol) werecombined in a reaction vessel and treated with isopropanol (6 mL). Thereaction vessel was sealed and the reaction was heated to 80° C. withstirring overnight. The reaction was cooled to room temperature. Theprecipitate was recovered by vacuum filtration, then treated withsaturated NaHCO_(3(aq)) and extracted three times with EtOAc. The EtOAcextracts were washed with brine, combined, dried over Na₂SO₄, filtered,concentrated under reduced pressure, and eluted through a 20 gram columnof silica gel with 99:1:0.1 CH₂Cl₂:MeOH:NH₄OH (1 liter). The recoveredmaterial was dissolved into MeOH and treated with 2 eq. of 6 NHCl_((aq)). This solution was concentrated under reduced pressure andthe recovered material was dissolved into hot isopropanol tore-crystallize. Crystals were recovered by vacuum filtration, washedwith a 20 isopropanol in hexane solution, and then with ether, thendried under vacuum giving 86 mg (48%) of an orange solid. LC-MS: RT=5.25min, [M+H]⁺=379.0.

EXAMPLE 71 Synthesis of3-(3-((5-(3-fluoro-2-(trifluoromethyl)phenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

Intermediate 5 (190 mg, 0.67 mmol) (prepared as described in Example 35)was dissolved into a 1:1 mixture of toluene (20 mL) and 1,4-dioxane (10mL) in a reaction vessel. 3-Fluoro-2-(trifluoromethyl)bromobenzene (326mg, 1.34 mmol), Pd(PPh₃)₄ (81 mg, 0.07 mmol), and 2 M Na₂CO_(3(aq)) (670μL, 1.34 mmol) were added and the reaction vessel flushed with N₂ andsealed. The reaction mixture was heated to 110° C. with stirringovernight. The reaction was then cooled to room temperature, filteredthrough celite®, and the filtrate concentrated under reduced pressure.The recovered material was then treated with water and extracted threetimes with EtOAc. The EtOAc extracts were washed with brine, combined,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Therecovered material was then eluted through a 20 gram column of silicagel with 98:2:0.2 CH₂Cl₂:MeOH:NH₄OH (1 liter). The material recoveredfrom this column was eluted through a second 20 gram column of silicagel with an 8.5:7:7:0.5:0.05 (685 mL) and with 7:7:7:1:0.1 (440 mL)Hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH step gradient. The recovered material wasdissolved into MeOH and treated with 2 eq. of 6 N HCl_((aq)). Thissolution was then concentrated under reduced pressure and the recoveredmaterial re-crystallized from a mixture of hot ethanol and isopropanol.The crystals were recovered by vacuum filtration and washed with a 20%solution of isopropanol in hexane, and then with ether, then dried undervacuum giving 29 mg (9%) of a golden yellow solid. LC-MS: RT=5.88 min,[M+H]⁺=401.0.

EXAMPLE 72 Synthesis of3-(3-(4-isopropoxy-2-methoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

(E)-3-(3-(4-isopropoxy-2-methoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride was prepared as described in Lepore, S. D.; He, Y. J.Org. Chem., 2003, 68, 8261-8263. Intermediate 4 (1.0 g, 2.7 mmol)(prepared as described in Example 22) was dissolved into water, treatedwith saturated NaHCO_(3(aq)), and extracted five times with CH₂Cl₂. TheCH₂Cl₂ extracts were washed with brine, combined, dried over Na₂SO₄,filtered and concentrated under reduced pressure and dried under vacuumgiving 705 mg (89%) of a yellow solid. PPh₃ (682 mg, 2.6 mmol),isopropanol (156 mg, 2.6 mmol) and DMF (2 mL) were added to this solidunder N₂ at room temperature. This mixture was then treated toultrasound (42 kHz, Branson brand 5510 sonicator) for 5 minutes. DIAD(526 mg, 2.6 mmol) was then added as the neat reagent, dropwise, viasyringe, over 8 minutes. This mixture was then treated to ultrasound atroom temperature under N₂, with occasional agitation of the reactionflask for 20 minutes. The reaction was quenched with water and extractedthree times with EtOAc. The EtOAc extracts were washed with brine,combined, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The recovered material was then eluted through a 50 gramcolumn of silica gel with the following step gradient: 99:1:0.1 (1liter); 98:2:0.2 (500 mL); 97:3:0.3 (500 mL); and 96:4:0.4 (500 mL)CH₂Cl₂:MeOH:NH₄OH. The material recovered from this column was dissolvedinto methanol and treated with 2 eq. of 6 N HCl_((aq)). This solutionwas concentrated under reduced pressure and the recovered materialdissolved into hot isopropanol and ethanol to re-crystallize. Thecrystals were recovered by vacuum filtration, washed with freshisopropanol, then dried under vacuum giving 203 mg (20%) of a yellowsolid. LC-MS: RT=5.49 min, [M+H]⁺=337.1.

EXAMPLE 73 Synthesis of3-(3-(4-isopropoxy-3-methoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride

3-(3-(4-Isopropoxy-3-methoxybenzylidene)-3,4,5,6-tetrahydropyridin-2-yl)pyridinedihydrochloride was prepared as described in Lepore, S. D.; He, Y. J.Org. Chem., 2003, 68, 8261-8263. Intermediate 3 (315 mg, 0.86 mmol)(prepared as described in Example 20) was treated with saturatedNaHCO_(3(aq)) and extracted three times with EtOAc. The EtOAc extractswere washed with brine, combined, dried over Na₂SO₄, filtered,concentrated under reduced pressure and dried under vacuum giving 241 mg(95%) of a red solid. PPh₃ (225 mg, 0.86 mmol), isopropanol (52 mg, 0.86mmol) and DMF (0.3 mL) were added to this mixture under N₂ at roomtemperature. This mixture was then treated to ultrasound (42 kHz,Branson brand 5510 sonicator) for several minutes. DIAD (174 mg, 0.86mmol) was then added as the neat reagent, dropwise, via syringe, underN₂, over 3 minutes. This mixture was then treated to ultrasound at roomtemperature, with occasional agitation of the reaction flask, for 20minutes. The reaction was quenched with water and extracted three timeswith EtOAc. The EtOAc extracts were washed with brine, combined, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Therecovered material was then eluted through a 50 gram column of silicagel with 99:1:0.1 CH₂Cl₂:MeOH:NH₄OH (3 liters). The material recoveredfrom this column was dissolved into methanol and treated with 2 eq. of 6N HCl_((aq)). This solution was concentrated under reduced pressure andthe recovered material dissolved into hot isopropanol to re-crystallize.The crystals were recovered by vacuum filtration, washed with freshisopropanol, and dried under vacuum giving 46 mg (13%) of a yellowsolid. LC-MS: RT=4.87 min, [M+H]⁺=337.1.

EXAMPLE 74 Synthesis of 6-(3-(naphthalen-1-ylmethylene)-3,4,56-tetrahydropyridin-2-yl)quinoline dihydrochloride.

Intermediate 15 (196 mg, 0.93 mmol) (prepared as described in Example55) was dissolved into isopropanol (6 mL) in a reaction vessel andtreated with 6 N HCl_((aq)) (310 μL, 1.9 mmol). 1-Naphthaldehyde (219mg, 1.4 mmol) was added, the reaction vessel was sealed, and thereaction heated to 85° C. with stirring overnight. The reaction wascooled to room temperature, concentrated under reduced pressure, treatedwith saturated NaHCO_(3(aq)), and extracted three times with EtOAc. TheEtOAc extracts were washed with brine, combined, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The recoveredmaterial was eluted through a 20 gram column of silica gel with a10.5:7:7:0.3:0.03 (750 mL) and 7:7:7:0.5:0.05 (300 mL)Hexane:MtBE:CH₂Cl₂:MeOH:NH₄OH step gradient. The material recovered fromthis column was then further purified by preparative HPLC using the sameconditions and method described for Example 47. The recovered materialwas dissolved into MeOH and treated with 2 eq. of 6 N HCl_((aq)). Thissolution was then concentrated under reduced pressure and the recoveredmaterial dissolved into hot isopropanol. After this solution had cooledto room temperature, ether was added until the solution became cloudy.This mixture was cooled to −20° C. Crystals did form and were recoveredby vacuum filtration, washed with fresh ether, and dried under vacuumgiving 31 mg (6.9%) of a brown solid. LC-MS: RT=5.45 min, [M+H]⁺=349.0.

EXAMPLES 75-114

A. Preparation of Intermediates 16-23

The compounds shown in Table 4 were prepared as described forIntermediate 2 in Example 29 using an appropriate aldehyde.

TABLE 4

Intermediate R_(a) R_(b) R_(c) R_(d) Yield LC RT MS [M + H]⁺ 16 H I H H63% 5.08 min 375.5 17 F Br H H 68% 4.95 min 345.4 18 H B(OH)₂ H H 72%3.51 min 293.4 19 F H Br H 26% 5.00 min 345.4 20 OCH₃ Br H H 65% 4.78min 357.5 21 H Br H OCH₃ 82% 22 H Br H H 64% 5.08 min 327.0 23 H H Br H65% 5.09 min 327.0B. The compounds shown in Table 5 were prepared as described for Example59, substituting Intermediates 16-23 for Intermediate 6 and using theappropriate arylhalide.

TABLE 5

LC MS Ex. R_(a) R_(b) R_(c) R_(d) Yield RT [M + H]⁺ 75 H

H H 41% 5.78 min 359.5 76 H

H H 42% 5.96 min 359.5 77 H

H H 15% 6.07 min 383.7 78 H

H H 57% 6.00 min 393.6 79 H

H H 29% 6.30 min 393.6 80 F

H H 40% 5.55 min 373.6 81 F

H H 54% 5.82 min 357.6 82 F

H H 35% 5.78 min 377.6 83 H

H H 33% 6.34 min 409.7 84 H

H H 14% 5.68 min 385.7 85 F H Ph H 51% 5.44 343.5 min 86 F H

H 66% 5.47 min 373.6 87 F H

H 54% 6.25 min 427.7 88 F H

H 34% 5.55 min 361.6 89 H

H H 38% 6.76 min 325.5 90 F

H H 35% 5.99 min 411.7 91 F

H H 62% 5.62 min 361.6 92 H

H H 12% 6.17 min 409.7 93 F

H H 37% 4.85 min 400.7 94 F

H H 50% 6.56 min 429.7 95 OCH₃

H H 30% 6.29 min 447.2 96 F

H H 37% 6.43 min 435.7 97 OCH₃

H H 53% 5.64 min 389.6 98 OCH₃

H H 39% 5.67 min 399.7 99 H

H OCH₃ 13% 6.00 min 399.7 100 OCH₃

H H 8% 5.78 min 417.2 101 H

H OCH₃ 33% 6.06 min 417.2 102 H Ph H H 38% 5.73 325.1 min 103 H

H H 25% 6.04 min 387.1 104 OCH₃ Ph H H 43% 5.47 355.1 min 105 H

H H 16% 6.19 min 359.1 106 OCH₃

H H 36% 5.63 min 373.1 107 H H

H 32% 5.54 min 355.1 108 OCH₃ H Ph H 34% 5.45 355.1 min 109 OCH₃

H H 10% 5.61 min 385.1 110 OCH₃

H H 17% 5.96 min 423.1 111 OCH₃

H H 26% 5.79 min 369.2 112 H

H H 10% 6.26 min 369.1 113 F Ph H H 14% 5.80 min 343.1 114 F

H H 50% 6.13 min 387.1

While this invention has been particularly shown and described withreferences to example embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound of the following formula:

or a pharmaceutically acceptable salt thereof, wherein: Each D isindependently selected from the group consisting of C1-C10 alkyl, C1-C10alkyl substituted with one or more R₈, C2-C10 alkenyl, C2-C10 alkenylsubstituted with one or more R₈, C2-C10 alkynyl, C2-C10 alkynylsubstituted with one or more R₈, C3-C10 cycloalkyl, C3-C10 cycloalkylsubstituted with one or more R₉, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₉, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₉, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₉, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₉, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₉,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₉, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₉,halo, haloalkyl, OR₇, SR₇, NR₇R₇, C(O)OR₇, NO₂, CN, C(O)R₇, C(O)C(O)R₇,C(O)NR₇R₇, C(O)C(O)NR₇R₇, N(R₇)C(O)R₇, NR₇S(O)_(q)R₇, N(R₇)C(O)OR₇,NR₇C(O)C(O)R₇, NR₇C(O)NR₇R₇, NR₇S(O)_(q)NR₇R₇, NR₇S(O)_(q)R₇,S(O)_(q)R₇, S(O)_(q)NR₇R₇, OC(O)R₇, aryl and heteroaryl, wherein saidaryl and heteroaryl are each optionally substituted with one or moreR₁₁; Each R₇ is independently selected from the group consisting of H,C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10cycloalkenyl, 3-10 membered heterocycloalkyl, 4-10 memberedheterocycloalkenyl, haloalkyl, aryl and heteroaryl, wherein said aryland heteroaryl are each optionally substituted with one or more R₁₁;Each R₈ is independently selected from the group consisting of halo,haloalkyl, OR₇, SR₇, C(O)R₇, OC(O)R₇, C(O)OR₇, NR₇R₇, NO₂, CN,OC(O)NR₇R₇, C(O)NR₇R₇, N(R₇)C(O)R₇, N(R₇)(COOR₇), S(O)_(q)NR₇R₇, C3-C8cycloalkyl, C4-C10 cycloalkenyl, 3-8 membered heterocycloalkyl, 4-10membered heterocycloalkenyl, C5-C11 bicycloalkyl, C5-C11 bicycloalkenyl,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkenyl,aryl and heteroaryl, wherein said aryl and heteroaryl are eachoptionally substituted with one or more R₁₁; Each R₉ is independentlyselected from the group consisting of R₈, C1-C10 alkyl, C1-C10 alkylsubstituted with one or more R₈, C2-C10 alkenyl, C2-C10 alkenylsubstituted with one or more R₈, C2-C10 alkynyl and C2-C10 alkynylsubstituted with one or more R₈; R₁₀ is aryl or heteroaryl, wherein saidaryl and heteroaryl are each optionally substituted with one or moreR₁₁; Each R₁₁ is independently selected from the group consisting ofC1-C10 alkyl, C1-C10 alkyl substituted with one or more R₈, C2-C10alkenyl, C2-C10 alkenyl substituted with one or more R₈, C2-C10 alkynyl,C2-C10 alkynyl substituted with one or more R₈, C3-C10 cycloalkyl,C3-C10 cycloalkyl substituted with one or more R₉, C4-C10 cycloalkenyl,C4-C10 cycloalkenyl substituted with one or more R₉, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₉, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₉, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₉, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₉,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₉, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₉,halo, haloalkyl, OR₇, SR₇, NR₇R₇, C(O)OR₇, NO₂, CN, C(O)R₇, C(O)C(O)R₇,C(O)NR₇R₇, N(R₇)C(O)R₇, NR₇S(O)₂R₇, N(R₇)C(O)OR₇, NR₇C(O)C(O)R₇,NR₇C(O)NR₇R₇, NR₇S(O)_(q)NR₇R₇, NR₇S(O)_(q)R₇, S(O)_(q)R₇,S(O)_(q)NR₇R₇, OC(O)R₇, optionally substituted aryl and optionallysubstituted heteroaryl; k is an integer from 0 to 4; Each q isindependently 1 or
 2. 2. The compound of claim 1 wherein k is 0 or
 1. 3.The compound of claim 1 wherein R₁₀ is selected from the groupconsisting of 6 membered monocyclic aryl, 5 or 6 membered monocyclicheteroaryl comprising 1-3 heteroatoms, 8-12 membered bicyclic aryl, 8-12membered bicyclic heteroaryl comprising 1-6 heteroatoms, 11-14 memberedtricyclic aryl and 11-14 membered heteroaryl comprising 1-9 heteroatoms,wherein each of said heteroatoms is independently selected from thegroup consisting of O, N and S and wherein each of said aryl andheteroaryl is optionally substituted with one or more R₁₁.
 4. Thecompound of claim 3 wherein R₁₀ is selected from the group consisting of6 membered monocyclic aryl and 5 or 6 membered monocyclic heteroarylcomprising 1-3 heteroatoms, wherein each of said heteroatoms isindependently selected from O, S and N, and wherein each of said aryland heteroaryl is optionally substituted with one or more R₁₁.
 5. Thecompound of claim 4 wherein the compound is methyl3-(5-((5,6-dihydro-2-(pyridin-3(4H)-ylidene)methylfuran-2-yl)thiophene-2-carboxylate.6. The compound of claim 4 wherein R₁₀ is:


7. The compound of claim 6 wherein there is an R₁₁ substitution at the2-position of the phenyl ring.
 8. The compound of claim 7 wherein thecompound is selected from the group consisting of3-(3-(2,5-dichlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3,4,5,6-tetrahydro-3-((5-(2-trifluoromethoxy)phenyl)furan-2-yl)methylene)pyridin-2-yl)pyridine,3-3-((5-(2-chloro-5-(trifluoromethyl)phenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-2-chloro-4-(trifluoromethyl)phenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-(2,4-dichlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-(4-chloro-2-nitrophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-(2-fluorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-o-tolylfuran-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-(2-chlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-(2-trifluoromethyl)phenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-(2,4-dimethoxyphenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridineand3-(3-((5-(2-fluoro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine.9. The compound of claim 6 wherein the compound is selected from thegroup consisting of3-(3-((5-phenylfuran-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-(4-chlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-(3-chlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-(3,4-dichlorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-(3-chloro-4-methoxyphenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-(3,5-bis(trifluoromethyl)phenyl)furan-2-yl)methylene-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-(5-(4-fluoro-3-(trifluormethyl)phenyl)furan-2-yl)methylene-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3,4,5,6-tetrahydro-3-((5-(2-nitrophenyl)furan-2-yl)methylene)pyridin-2-yl)pyridine,3-(3,4,5,6-tetrahydro-3-((5-(3-nitrophenyl)furan-2-yl)methylene)pyridin-2-yl)pyridine,3-(3-((5-(4-chloro-2-nitrophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-(5-(4-fluorophenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyridin-2-yl)pyridine,3-(3-((5-(2-chloro-5-(trifluoromethyl)phenyl)furan-2-yl)methylene)-3,4,5,6-tetrahydropyrdin-2-yl)pyridine,3-(3,4,5,6-tetrahydro-3-((5,6-(trifluoromethoxy)phenyl)furan-2-yl)methylene)pyridin-2-yl)pyridineand3-(3-((5-(3-(trifluoromethyl)phenyl)furan-2-yl)methylene-3,4,5,6-tetrahydropyridin-2-yl)pyridine10. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and an effective amount of a compound of claim 1.